Azolidinone-vinyl fused-benzene derivatives

ABSTRACT

The present invention is related to azolidinedione-vinyl fused-benzene derivatives of formula (I) for the treatment and/or prophylaxis of autoimmune disorders and/or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, kidney diseases, platelet aggregation, cancer, graft rejection or lung injuries. Formula (I), wherein A, X, Y, Z, R 1 , R 2  and n are as described in the description.

FIELD OF THE INVENTION

This present invention is related to the use of azolidinone-vinylfused-benzene derivatives of formula (I) for the treatment and/orprophylaxis of autoimmune disorders and/or inflammatory diseases,cardiovascular diseases, neurodegenerative diseases, bacterial or viralinfections, kidney diseases, platelet aggregation, cancer, graftrejection or lung injuries. Specifically, the present invention isrelated to substituted azolidinone-vinyl fused-benzene derivatives forthe modulation, notably the inhibition of the activity or function ofthe phospho-inositide-3′OH kinase family, PI3K, particularly of thePI3Kγ.

BACKGROUND OF THE INVENTION

Cellular plasma membranes can be viewed as a large store of secondmessenger that can be enlisted in a variety of signal transductionpathways. As regards function and regulation of effector enzymes inphospholipid signalling pathways, these enzymes generate secondmessengers from the membrane phospholipid pool (class I PI3 kinases(e.g. PI3Kgamma)) are dual-specific kinase enzymes, means they displayboth: lipid kinase (phosphorylation of phospho-inositides) as well asprotein kinase activity, shown to be capable of phosphorylation of otherprotein substrates, including auto-phosphorylation as intra-molecularregulatory mechanism. These enzymes of phospholipid signalling areactivated in response to a variety of extra-cellular signals such asgrowth factors, mitogens, integrins (cell-cell interactions) hormones,cytokines, viruses and neurotransmitters such as described in Scheme 1hereinafter and also by intra-cellular cross regulation by othersignaling molecules (cross-talk, where the original signal can activatesome parallel pathways that in a second step transmit signals to PI3Ksby intra-cellular signaling events), such as small GTPasesu, kinases orphosphatases for example.

The inositol phospholipids (phosphoinositides) intracellular signallingpathway begins with binding of a signalling molecule (extracellularligands, stimuli, receptor dimerization, transactivation by heterologousreceptor (e.g. receptor tyrosine kinase)) to a G-protein linkedtransmembrane receptor integrated into the plasma membrane.

PI3K converts the membrane phospholipid PIP(4,5)2 into PIP(3,4,5)3 whichin turn can be further converted into another 3′ phosphorylated form ofphosphoinositides by 5′-specific phospho-inositide phosphatases, thusPI3K enzymatic activity results either directly or indirectly in thegeneration of two 3′-phosphoinositide subtypes that function as 2^(nd)messengers in intra-cellular signal transduction (Trends Biochem Sci.22(7) p. 267-72 (1997) by Vanhaesebroeck B et al., Chem Rev. 101(8) p.2365-80 (2001) by Leslie N. R et al (2001); Annu Rev Cell Dev Biol. 17p. 615-75 (2001) by Katso R. et al. and Cell Mol Life Sci. 59(5) p.761-79 (2002) by Toker a. et al.). Multiple PI3K isoforms categorized bytheir catalytic subunits, their regulation by corresponding regulatorysubunits, expression patterns and signaling-specific functions (p110α,β, δ, and γ) perform this enzymatic reaction (Exp Cell Res. 25(1) p.239-54 (1999) by Vanhaesebroeck B. and Annu Rev Cell Dev Biol. 17 p.615-75 (2001) by Katso R. et al).

The evolutionary conserved isoforms p110α and β are ubiquitouslyexpressed, while δ and γ are more specifically expressed in thehaematopoietic cell system, smooth muscle cells, myocytes andendothelial cells (Trends Biochem Sci. 22(7) p. 267-72 (1997) byVanhaesebroeck B et al.). Their expression might also be regulated in aninducible manner depending on the cellular-, tissue type and stimuli aswell as disease context. To date, eight mammalian PI3Ks have beenidentified, divided into three main classes (I, II, and III) on thebasis of sequence homology, structure, binding partners, mode ofactivation, and substrate preference in vitro. Class I PI3Ks canphosphorylate phosphatidylinositol (PI),phosphatidylinositol-4-phosphate, andphosphatidylinositol-4,5-biphosphate (PIP2) to producephosphatidylinositol-3-phosphate (PIP),phosphatidylinositol-3,4-biphosphate, andphosphatidylinositol-3,4,5-triphosphate, respectively. Class II PI3Ksphosphorylate PI and phosphatidylinositol-4-phosphate. Class III PI3Kscan only phosphorylate PI (Trends Biochem Sci. 22(7) p. 267-72 (1997) byVanhaesebroeck B et al, Exp Cell Res. 25(1) p. 239-54 (1999) byVanhaesebroeck B. and Chem Rev. 101(8) p. 2365-80 (2001) by Leslie N. Ret al (2001)) G-protein coupled receptors mediated phosphoinositide3′OH-kinase activation via small GTPases such as Gβγ and Ras, andconsequently PI3K signaling plays a central role in establishing andcoordinating cell polarity and dynamic organization of thecytoskeleton—which together provides the driving force of cells to move.

As above illustrated in Scheme 1, Phosphoinositide 3-kinase (PI3K) isinvolved in the phosphorylation of Phosphatidylinositol (PtdIns) on thethird carbon of the inositol ring. The phosphorylation of PtdIns to3,4,5-triphosphate (PtdIns(3,4,5)P₃), PtdIns(3,4)P₂ and PtdIns(3)P actas second messengers for a variety of signal transduction pathways,including those essential to cell proliferation, cell differentiation,cell growth, cell size, cell survival, apoptosis, adhesion, cellmotility, cell migration, chemotaxis, invasion, cytoskeletalrearrangement, cell shape changes, vesicle trafficking and metabolicpathway (Annu Rev Cell Dev Biol. 17 p. 615-75 (2001) by Katso et al. andMol Med Today 6(9) p. 347-57 (2000) by Stein R. C). Chemotaxis—thedirected movement of cells toward a concentration gradient of chemicalattractants, also called chemokines is involved in many importantdiseases such as inflammation/auto-immunity, neurodegeneration,angiogenesis, invasion/metastisis and wound healing (Immunol Today 21(6)p. 260-4 (2000) by Wyman N P et al.; Science 287(5455) p. 1049-53 (2000)by Hirsch et al.; FASEB J 15(11) p. 2019-21 (2001) by Hirsch et al. andNat Immunol. 2(2) p. 108-15 (2001) by Gerard C. et al.).

Recent advances using genetic approaches and pharmacological tools haveprovided insights into signaling and molecular pathways that mediatechemotaxis in response to chemoattractant activated G-protein coupledreceptors PI3-Kinase, responsible for generating these phosphorylatedsignalling products, was originally identified as an activity associatedwith viral oncoproteins and growth factor receptor tyrosine kinases thatphosphorylates phosphatidylinositol (PI) and its phosphorylatedderivatives at the 3′-hydroxyl of the inositol ring (Panayotou et al.,Trends Cell Biol. 2 p. 358-60 (1992)). However, more recent biochemicalstudies revealed that, class I PI3 kinases (e.g. class IB isoform PI3Kγ)are dual-specific kinase enzymes, means they display both: lipid kinase(phosphorylation of phospho-inositides) as well as protein kinaseactivity, shown to be capable of phosphorylation of other protein assubstrates, including auto-phosphorylation as intra-molecular regulatorymechanism.

So, PI3-kinase activation, therefore, is believed to be involved in arange of cellular responses including cell growth, differentiation, andapoptosis (Parker et al., Current Biology, 5 p. 577-99 (1995), Yao etal., Science, 267 p. 2003-05 (1995)).

PI3-kinase appears to be involved in a number of aspects of leukocyteactivation. A p85-associated PI3-kinase activity has been shown tophysically associate with the cytoplasmic domain of CD28, which is animportant costimulatory molecule for the activation of T-cells inresponse to antigen (Pages et al., Nature, 369 p, 327-29 (1994); Rudd,Immunity 4 p. 527-34 (1996)). Activation of T cells through CD28 lowersthe threshold for activation by antigen and increases the magnitude andduration of the proliferative response. These effects are linked toincreases in the transcription of a number of genes includinginterleukin-2 (IL2), an important T cell growth factor (Fraser et al.,Science, 251 p. 313-16 (1991)). Mutation of CD28 such that it can longerinteract with PI3-kinase leads to a failure to initiate IL2 production,suggesting a critical role for PI3-kinase in T cell activation. PI3Kγhas been identified as a mediator of G beta-gamma-dependent regulationof JNK activity, and G beta-gamma are subunits of heterotrimeric Gproteins (J. Biol. Chem. 273(5) p. 2505-8 (1998). Cellular processes inwhich PI3Ks play an essential role include suppression of apoptosis,reorganization of the actin skeleton, cardiac myocyte growth, glycogensynthase stimulation by insulin, TNFα-mediated neutrophil priming andsuperoxide generation, and leukocyte migration and adhesion toendothelial cells. Recently, (Immunity 16(3) p. 441-51 (2002)) it hasbeen described that PI3Kγ relays inflammatory signals through variousG(i)-coupled receptors and its central to mast cell function, stimuli incontext of leukocytes, immunology includes cytokines, chemokines,adenosines, antibodies, integrins, aggregation factors, growth factors,viruses or hormones for example (J. Cell. Sci 114(Pt 16) p. 2903-10(2001) by Lawlor M A et al., Immunity 16(3) p. 441-51 (2002) byLaffargue M. et al. and Curr. Opinion Cell Biol. 14(2) p. 203-13 (2002)by Stephens L. et al.).

Specific inhibitors against individual members of a family of enzymesprovide invaluable tools for deciphering functions of each enzyme. Twocompounds, LY294002 and wortmannin (cf.hereinafter), have been widelyused as PI3-kinase inhibitors. These compounds are non-specific PI3Kinhibitors, as they do not distinguish among the four members of Class IPI3-kinases. For example, the IC₅₀ values of wortmannin against each ofthe various Class I PI3-kinases are in the range of 1-10 nM. Similarly,the IC₅₀ values for LY294002 against each of these PI3-kinases is about15-20 μM (Fruman et al., An. Rev. Biochem., 67 p. 481-507 (1998)), also5-10 microM on CK2 protein kinase and some inhibitory activity onphospholipases. Wortmannin is a fungal metabolite which irreversiblyinhibits PI3K activity by binding covalently to the catalytic domain ofthis enzyme. Inhibition of PI3K activity by wortmannin eliminates thesubsequent cellular response to the extracellular factor. For example,neutrophils respond to the chemokine fMet-Leu-Phe (fMLP) by stimulatingPI3K and synthesizing PtdIns (3, 4, 5)P₃. This synthesis correlates withactivation of the respirators burst involved in neutrophil destructionof invading microorganisms. Treatment of neutrophils with wortmanninprevents the fMLP-induced respiratory burst response (Thelen et al. PNAS91 p. 4960-64 (1994)). Indeed, these experiments with wortmannin, aswell as other experimental evidence, shows that PI3K activity in cellsof hematopoietic lineage, particularly neutrophils, monocytes, and othertypes of leukocytes, is involved in many of the non-memory immuneresponse associated with acute and chronic inflammation.

Based on studies using wortmannin, there is evidence that PI3-kinasefunction also is required for some aspects of leukocyte signalingthrough G-protein coupled receptors (Thelen et al., Proc. Natl. Acad.Sci. USA, 91 p. 4960-64 (1994)). Moreover, it has been shown thatwortmannin and LY294002 block neutrophil migration and superoxiderelease. However, in as much as these compounds do not distinguish amongthe various isoforms of PI3K, it remains unclear which particular PI3Kisoform or isoforms are involved in these phenomena.

Azolidinone-vinyl benzene derivatives—having a mandatory benzimidazolemoiety though—are described in WO 02/051409. The compounds are said toinhibit telomerase and are purportedly useful in the treatment ofcancer.

SUMMARY OF THE INVENTION

The present invention relates to the use of azolidinone-vinylfused-benzene derivatives of formula (I)

wherein A, X, Y, Z, n, R¹ and R² are described in details in thedescription hereinafter, as well as pharmaceutically acceptable saltsthereof, for the preparation of pharmaceutical compositions for thetreatment and/or prophylaxis of autoimmune disorders and/or inflammatorydiseases, cardiovascular diseases, neurodegenerative diseases, bacterialor viral infections, kidney diseases, platelet aggregation, cancer,transplantation complications, graft rejection or lung injuries.Compounds of this invention are inhibitors of Phosphato-inositides3-kinases (PI3Ks), particularly of Phosphatoinositides 3-kinases gamma(PI3Kγ).

DESCRIPTION OF THE INVENTION

It has now been found that compounds of the present invention aremodulators of the Phosphatoinositides 3-kinases (PI3Ks), particularly ofPhosphatoinositides 3-kinase γ (PI3Kγ). When the phosphatoinositides3-kinase (PI3K) enzyme is inhibited by the compounds of the presentinvention, PI3K is unable to exert its enzymatic, biological and/orpharmacological effects. The compounds of the present invention aretherefore useful in the treatment and prevention of autoimmune disordersand/or inflammatory diseases, cardiovascular diseases, neurodegenerativediseases, bacterial or viral infections, kidney diseases, plateletaggregation, cancer, transplantation complications, graft rejection orlung injuries.

The following paragraphs provide definitions of the various chemicalmoieties that make up the compounds according to the invention and areintended to apply uniformly through-out the specification and claimsunless an otherwise expressly set out definition provides a broaderdefinition.

“C₁-C₆-alkyl” refers to monovalent alkyl groups having 1 to 6 carbonatoms. This term is exemplified by groups such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyland the like.

“Aryl” refers to an unsaturated aromatic carbocyclic group of from 6 to14 carbon atoms having a single ring (e.g., phenyl) or multiplecondensed rings (e.g., naphthyl). Preferred aryl include phenyl,naphthyl, phenantrenyl and the like.

“C₁-C₆-alkyl aryl” refers to C₁-C₆-alkyl groups having an arylsubstituent, including benzyl, phenethyl and the like.

“Heteroaryl” refers to a monocyclic heteroaromatic, or a bicyclic or atricyclic fused-ring heteroaromatic group. Particular examples ofheteroaromatic groups include optionally substituted pyridyl, pyrrolyl,furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl,[2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl,isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl,imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxazolyl, quinolizinyl,quinazolinyl, pthalazinyl, quinoxalinyl, cinnolinyl, napthyridinyl,pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl,quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl,5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl,xanthenyl or benzoquinolyl.

“C₁-C₆-alkyl heteroaryl” refers to C₁-C₆-alkyl groups having aheteroaryl substituent, including 2-furylmethyl, 2-thienylmethyl,2-(1H-indol-3-yl)ethyl and the like.

“C₂-C₆-alkenyl” refers to alkenyl groups preferably having from 2 to 6carbon atoms and having at least 1 or 2 sites of alkenyl unsaturation.Preferable alkenyl groups include ethenyl (—CH═CH₂), n-2-propenyl(allyl, —CH₂CH═CH₂) and the like.

“C₂-C₆-alkenyl aryl” refers to C₂-C₆-alkenyl groups having an arylsubstituent including 2-phenylvinyl and the like.

“C₂-C₆-alkenyl heteroaryl” refers to C₂-C₆-alkenyl groups having aheteroaryl substituent, including 2-(3-pyridinyl)vinyl and the like.

“C₂-C₆-alkynyl” refers to alkynyl groups preferably having from 2 to 6carbon atoms and having at least 1-2 sites of alkynyl unsaturation,preferred alkynyl groups include ethynyl (—C≡CH), propargyl (—CH₂C≡CH),and the like.

“C₂-C₆-alkynyl aryl” refers to C₂-C₆-alkynyl groups having an arylsubstituent, including phenylethynyl and the like.

“C₂-C₆-alkynyl heteroaryl” refers to C₂-C₆-alkynyl groups having aheteroaryl substituent, including 2-thienylethynyl and the like.

“C₃-C₈-cycloalkyl” refers to a saturated carbocyclic group of from 3 to8 carbon atoms having a single ring (e.g., cyclohexyl) or multiplecondensed rings (e.g., norbornyl). Preferred cycloalkyl includecyclopentyl, cyclohexyl, norbornyl and the like.

“Heterocycloalkyl” refers to a C₃-C₈-cycloalkyl group according to thedefinition above, in which up to 3 carbon atoms are replaced byheteroatoms chosen from the group consisting of O, S, NR, R beingdefined as hydrogen or methyl. Preferred heterocycloalkyl includepyrrolidine, piperidine, piperazine, 1-methylpiperazine, morpholine, andthe like.

“C₁-C₆-alkyl cycloalkyl” refers to C₁-C₆-alkyl groups having acycloalkyl substituent, including cyclohexylmethyl, cyclopentylpropyl,and the like.

“C₁-C₆-alkyl heterocycloalkyl” refers to C₁-C₆-alkyl groups having aheterocycloalkyl substituent, including 2-(1-pyrrolidinyl)ethyl,4-morpholinylmethyl, (1-methyl-4-piperidinyl)methyl and the like.

“Carboxy” refers to the group —C(O)OH.

“C₁-C₆-alkyl carboxy” refers to C₁-C₆-alkyl groups having an carboxysubstituent, including 2-carboxyethyl and the like.

“Acyl” refers to the group —C(O)R where R includes “C₁-C₆-alkyl”,“aryl”, “heteroaryl”, “C₁-C₆-alkyl aryl” or “C₁-C₆-alkyl heteroaryl”.

“C₁-C₆-alkyl acyl” refers to C₁-C₆-alkyl groups having an acylsubstituent, including 2-acetylethyl and the like.

“Aryl acyl” refers to aryl groups having an acyl substituent, including2-acetylphenyl and the like.

“Heteroaryl acyl” refers to hetereoaryl groups having an acylsubstituent, including 2-acetylpyridyl and the like.

“C₃-C₈-(hetero)cycloalkyl acyl” refers to 3 to 8 membered cycloalkyl orheterocycloalkyl groups having an acyl substituent.

“Acyloxy” refers to the group —OC(O)R where R includes H, “C₁-C₆-alkyl”,“C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”, “C₃-C₈-cycloalkyl”, heterocycloalkyl“heterocycloalkyl”, “aryl”, “heteroaryl”, “C₁-C₆-alkyl aryl” or“C₁-C₆-alkyl heteroaryl”, “C₂-C₆-alkenyl aryl”, “C₂-C₆-alkenylheteroaryl”, “C₂-C₆-alkynyl aryl”, “C₂-C₆-alkynylheteroaryl”,“C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkyl heterocycloalkyl”.

“C₁-C₆-alkyl acyloxy” refers to C₁-C₆-alkyl groups having an acyloxysubstituent, including 2-(acetyloxy)ethyl and the like.

“Alkoxy” refers to the group —O—R where R includes “C₁-C₆-alkyl” or“aryl” or “heteroaryl” or “C₁-C₆-alkyl aryl” or “C₁-C₆-alkylheteroaryl”. Preferred alkoxy groups include by way of example, methoxy,ethoxy, phenoxy and the like.

“C₁-C₆-alkyl alkoxy” refers to C₁-C₆-alkyl groups having an alkoxysubstituent, including 2-ethoxyethyl and the like.

“Alkoxycarbonyl” refers to the group —C(O)OR where R includes H,“C₁-C₆-alkyl” or “aryl” or “heteroaryl” or “C₁-C₆-alkyl aryl” or“C₁-C₆-alkyl heteroaryl”.

“C₁-C₆-alkyl alkoxycarbonyl” refers to C₁-C₅-alkyl groups having analkoxycarbonyl substituent, including 2-(benzyloxycarbonyl)ethyl and thelike.

“Aminocarbonyl” refers to the group —C(O)NRR′ where each R, R′ includesindependently hydrogen or C₁-C₆-alkyl or aryl or heteroaryl or“C₁-C₆-alkyl aryl” or “C₁-C₆-alkyl heteroaryl”.

“C₁-C₆-alkyl aminocarbonyl” refers to C₁-C₆-alkyl groups having anaminocarbonyl substituent, including 2-(dimethylaminocarbonyl)ethyl andthe like.

“Acylamino” refers to the group —NRC(O)R′ where each R, R′ isindependently hydrogen, “C₁-C₆-alkyl”, “C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”,“C₃-C₈-cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”,“C₁-C₆-alkyl aryl” or “C₁-C₆-alkyl heteroaryl”, “C₂-C₆-alkenyl aryl”,“C₂-C₆-alkenyl heteroaryl”, “C₂-C₆-alkynyl aryl”,“C₂-C₆-alkynylheteroaryl”, “C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkylheterocycloalkyl”.

“C₁-C₆-alkyl acylamino” refers to C₁-C₆-alkyl groups having an acylaminosubstituent, including 2-(propionylamino)ethyl and the like.

“Ureido” refers to the group —NRC(O)NR′R″ where each R, R′, R″ isindependently hydrogen, “C₁-C₆-alkyl”, “C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”,“C₃-C₈-cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”,“C₁-C₆-alkyl aryl” or “C₁-C₆-alkyl heteroaryl”, “C₂-C₆-alkenyl aryl”,“C₂-C₆-alkenyl heteroaryl”, “C₂-C₆-alkynyl aryl”,“C₂-C₆-alkynylheteroaryl”, “C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkylheterocycloalkyl”, and where R′ and R″, together with the nitrogen atomto which they are attached, can optionally form a 3-8-memberedheterocycloalkyl ring.

“C₁-C₆-alkyl ureido” refers to C₁-C₆-alkyl groups having an ureidosubstituent, including 2-(N′-methylureido)ethyl and the like.

“Carbamate” refers to the group —NRC(O)OR′ where each R, R′ isindependently hydrogen, “C₁-C₆-alkyl”, “C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”,“C₃-C₈-cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”,“C₁-C₆-alkyl aryl” or “C₁-C₆-alkyl heteroaryl”, “C₂-C₆-alkenyl aryl”,“C₂-C₆-alkenyl heteroaryl”, “C₂-C₆-alkynyl aryl”,“C₂-C₆-alkynylheteroaryl”, “C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkylheterocycloalkyl”.

“Amino” refers to the group —NRR′ where each R,R′ is independentlyhydrogen or “C₁-C₆-alkyl” or “aryl” or “heteroaryl” or “C₁-C₆-alkylaryl” or “C₁-C₆-alkyl heteroaryl”, or “cycloalkyl”, or“heterocycloalkyl”, and where R and R′, together with the nitrogen atomto which they are attached, can optionally form a 3-8-memberedheterocycloalkyl ring.

“C₁-C₆-alkyl amino” refers to C₁-C₅-alkyl groups having an aminosubstituent, including 2-(1-pyrrolidinyl)ethyl and the like.

“Ammonium” refers to a positively charged group —N⁺RR′R″, where eachR,R′,R″ is independently “C₁-C₆-alkyl” or “C₁-C₆-alkyl aryl” or“C₁-C₆-alkyl heteroaryl”, or “cycloalkyl”, or “heterocycloalkyl”, andwhere R and R′, together with the nitrogen atom to which they areattached, can optionally form a 3-8-membered heterocycloalkyl ring.

“C₁-C₆-alkyl ammonium” refers to C₁-C₆-alkyl groups having an ammoniumsubstituent, including 2-(1-pyrrolidinyl)ethyl and the like.

“Halogen” refers to fluoro, chloro, bromo and iodo atoms.

“Sulfonyloxy” refers to a group —OSO₂—R wherein R is selected from H,“C₁-C₆-alkyl”, “C₁-C₆-alkyl” substituted with halogens, e.g., an—OSO₂—CF₃ group, “C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”, “C₃-C₈-cycloalkyl”,“heterocycloalkyl”, “aryl”, “heteroaryl”, “C₁-C₆-alkyl aryl” or“C₁-C₆-alkyl heteroaryl”, “C₂-C₆-alkenyl aryl”, “C₂-C₆-alkenylheteroaryl”, “C₂-C₆-alkynyl aryl”, “C₂-C₆-alkynylheteroaryl”,“C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkyl heterocycloalkyl”.

“C₁-C₆-alkyl sulfonyloxy” refers to C₁-C₅-alkyl groups having asulfonyloxy substituent, including 2-(methylsulfonyloxy)ethyl and thelike.

“Sulfonyl” refers to group “—SO₂—R” wherein R is selected from H,“aryl”, “heteroaryl”, “C₁-C₆-alkyl”, “C₁-C₆-alkyl” substituted withhalogens, e.g., an —SO₂—CF₃ group, “C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”,“C₃-C₈-cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”,“C₁-C₆-alkyl aryl” or “C₁-C₆-alkyl heteroaryl”, “C₂-C₆-alkenyl aryl”,“C₂-C₆-alkenyl heteroaryl”, “C₂-C₆-alkynyl aryl”,“C₂-C₆-alkynylheteroaryl”, “C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkylheterocycloalkyl”.

“C₁-C₆-alkyl sulfonyl” refers to C₁-C₅-alkyl groups having a sulfonylsubstituent, including 2-(methylsulfonyl)ethyl and the like.

“Sulfinyl” refers to a group “—S(O)—R” wherein R is selected from H,“C₁-C₆-alkyl”, “C₁-C₆-alkyl” substituted with halogens, e.g., a —SO—CF₃group, “C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”, “C₃-C₈-cycloalkyl”,“heterocycloalkyl”, “aryl”, “heteroaryl”, “C₁-C₆-alkyl aryl” or“C₁-C₆-alkyl heteroaryl”, “C₂-C₆-alkenyl aryl”, “C₂-C₆-alkenylheteroaryl”, “C₂-C₆-alkynyl aryl”, “C₂-C₆-alkynylheteroaryl”,“C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkyl heterocycloalkyl”.

“C₁-C₆-alkyl sulfinyl” refers to C₁-C₅-alkyl groups having a sulfinylsubstituent, including 2-(methylsulfinyl)ethyl and the like.

“Sulfanyl” refers to groups —S—R where R includes H, “C₁-C₆-alkyl”,“C₁-C₆-alkyl” substituted with halogens, e.g., a —SO—CF₃ group,“C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”, “C₃-C₈-cycloalkyl”,“heterocycloalkyl”, “aryl”, “heteroaryl”, “C₁-C₆-alkyl aryl” or“C₁-C₆-alkyl heteroaryl”, “C₂-C₆-alkenyl aryl”, “C₂-C₆-alkenylheteroaryl”, “C₂-C₆-alkynyl aryl”, “C₂-C₆-alkynylheteroaryl”,“C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkyl heterocycloalkyl”. Preferredsulfanyl groups include methylsulfanyl, ethylsulfanyl, and the like.

“C₁-C₆-alkyl sulfanyl” refers to C₁-C₅-alkyl groups having a sulfanylsubstituent, including 2-(ethylsulfanyl)ethyl and the like.

“Sulfonylamino” refers to a group —NRSO₂—R′ where each R, R′ includesindependently hydrogen, “C₁-C₆-alkyl”, “C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”,“C₃-C₈-cycloalkyl”, “heterocycloalkyl”, “aryl”; “heteroaryl”,“C₁-C₆-alkyl aryl” or “C₁-C₆-alkyl heteroaryl”, “C₂-C₆-alkenyl aryl”,“C₂-C₆-alkenyl heteroaryl”, “C₂-C₆-alkynyl aryl”,“C₂-C₆-alkynylheteroaryl”, “C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkylheterocycloalkyl”.

“C₁-C₆-alkyl sulfonylamino” refers to C₁-C₅-alkyl groups having asulfonylamino substituent, including 2-(ethylsulfonylamino)ethyl and thelike.

“Aminosulfonyl” refers to a group SO₂—NRR′ where each R, R′ includesindependently hydrogen, “C₁-C₆-alkyl”, “C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”,“C₃-C₈-cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”,“C₁-C₆-alkyl aryl” or “C₁-C₆-alkyl heteroaryl”, “C₂-C₆-alkenyl aryl”,“C₂-C₆-alkenyl heteroaryl”, “C₂-C₆-alkynyl aryl”,“C₂-C₆-alkynylheteroaryl”, “C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkylheterocycloalkyl”.

“C₁-C₆-alkyl aminosulfonyl” refers to C₁-C₆-alkyl groups having anaminosulfonyl substituent, including 2-(cyclohexylaminosulfonyl)ethyland the like.

“Substituted or unsubstituted”: Unless otherwise constrained by thedefinition of the individual substituent, the above set out groups, like“alkyl”, “alkenyl”, “alkynyl”, “aryl” and “heteroaryl” etc. groups canoptionally be substituted with from 1 to 5 substituents selected fromthe group consisting of “C₁-C₆-alkyl”, “C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”,“cycloalkyl”, “heterocycloalkyl”, “C₁-C₆-alkyl aryl”, “C₁-C₆-alkylheteroaryl”, “C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkyl heterocycloalkyl”,“amino”, “ammonium”, “acyl”, “acyloxy”, “acylamino”, “aminocarbonyl”,“alkoxycarbonyl”, “ureido”, “aryl”, “carbamate”, “heteroaryl”,“sulfinyl”, “sulfonyl”, “alkoxy”, “sulfanyl”, “halogen”, “carboxy”,trihalomethyl, cyano, hydroxy, mercapto, nitro, and the like.Alternatively said substitution could also comprise situations whereneighbouring substituents have undergone ring closure, notably whenvicinal functional substituents are involved, thus forming, e.g.,lactams, lactons, cyclic anhydrides, but also acetals, thioacetals,aminals formed by ring closure for instance in an effort to obtain aprotective group.

“Pharmaceutically acceptable cationic salts or complexes” is intended todefine such salts as the alkali metal salts, (e.g. sodium andpotassium), alkaline earth metal salts (e.g. calcium or magnesium),aluminium salts, ammonium salts and salts with organic amines such aswith methylamine, dimethylamine, trimethylamine, ethylamine,triethylamine, morpholine, N-Me-D-glucamine,N,N′-bis(phenylmethyl)-1,2-ethanediamine, ethanolamine, diethanolamine,ethylenediamine, N-methylmorpholine, piperidine, benzathine(N,N′-dibenzylethylenediamine), choline, ethylene-diamine, meglumine(N-methylglucamine), benethamine (N-benzylphenethylamine), diethylamine,piperazine, thromethamine (2-amino-2-hydroxymethyl-1,3-propanediol),procaine as well as amines of formula —NR,R′,R″ wherein R,R′,R″ isindependently hydrogen, alkyl or benzyl. Especially preferred salts aresodium and potassium salts.

“Pharmaceutically acceptable salts or complexes” refers to salts orcomplexes of the below-identified compounds of the present inventionthat retain the desired biological activity. Examples of such saltsinclude, but are not restricted to acid addition salts formed withinorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuricacid, phosphoric acid, nitric acid, and the like), and salts formed withorganic acids such as acetic acid, oxalic acid, tartaric acid, succinicacid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoicacid, tannic acid, pamoic acid, alginic acid, polyglutamic acid,naphthalene sulfonic acid, naphthalene disulfonic acid, andpoly-galacturonic acid. Said compounds can also be administered aspharmaceutically acceptable quaternary salts known by a person skilledin the art, which specifically include the quarternary ammonium salt ofthe formula —NR,R′,R″⁺ Z⁻, wherein R, R′, R″ is independently hydrogen,alkyl, or benzyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-alkylaryl, C₁-C₆-alkyl heteroaryl, cycloalkyl, heterocycloalkyl, and Z is acounterion, including chloride, bromide, iodide, —O-alkyl,toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate(such as benzoate, succinate, acetate, glycolate, maleate, malate,fumarate, citrate, tartrate, ascorbate, cinnamoate, mandeloate, anddiphenylacetate).

“Pharmaceutically active derivative” refers to any compound that uponadministration to the recipient, is capable of providing directly orindirectly, the activity disclosed herein.

“Enantiomeric excess” (ee) refers to the products that are obtained byan asymmetric synthesis, i.e. a synthesis involving non-racemic startingmaterials and/or reagents or a synthesis comprising at least oneenantioselective step, whereby a surplus of one enantiomer in the orderof at least about 52% ee is yielded.

General formula (I) according to the present invention also comprisesits tautomers, its geometrical isomers, its optically active forms asenantiomers, diastereomers and its racemate forms, as well aspharmaceutically acceptable salts thereof. Preferred pharmaceuticallyacceptable salts of the formulae of the present invention are acidaddition salts formed with pharmaceutically acceptable acids likehydrochloride, hydrobromide, sulfate or bisulfate, phosphate or hydrogenphosphate, acetate, benzoate, succinate, fumarate, maleate, lactate,citrate, tartrate, gluconate, methanesulfonate, benzenesulfonate, andpara-toluenesulfonate salts.

The compounds of the present invention may be obtained as E/Z isomermixture or as essentially pure E-isomers or Z isomers. The E/Z isomerismpreferably refers to the vinyl moiety linking the phenyl with theazolidinone moiety. In a specific embodiment, the compounds of formula(I) are Z-isomers.

A first aspect of the present invention consists in the use of compoundsof formula (I)

as well as its geometrical isomers, its optically active forms asenantiomers, diastereomers and its racemate forms, as well aspharmaceutically acceptable salts and pharmaceutically activederivatives thereof for the preparation of a medicament for theprophylaxis and/or treatment of autoimmune disorders and/or inflammatorydiseases, cardiovascular diseases, neurodegenerative diseases, bacterialor viral infections, kidney diseases, platelet aggregation, cancer,transplantation complications due to rejection reactions, graftrejection or lung injuries.

In a preferred embodiment, these compounds are useful for the treatmentand/or prophylaxis of autoimmune diseases or inflammatory diseases suchas multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupuserythematosis, inflammatory bowel disease, lung inflammation, thrombosisor brain infection/inflammation such as meningitis or encephalitis.

In another preferred embodiment according to the invention, thesecompounds are useful for the treatment and/or prophylaxis ofneurodegenerative diseases including multiple sclerosis, Alzheimer'sdisease, Huntington's disease, CNS trauma, stroke or ischemicconditions.

In a particularly preferred embodiment according to the invention, thesecompounds are useful for the treatment and/or prophylaxis ofcardiovascular diseases such as atherosclerosis, heart hypertrophy,cardiac myocyte dysfunction, elevated blood pressure orvasoconstriction.

In another particularly preferred embodiment according to the invention,these compounds are useful for the treatment and/or prophylaxis ofchronic obstructive pulmonary disease, anaphylactic shock fibrosis,psoriasis, allergic diseases, asthma, stroke or ischemic conditions,ischemia-reperfusion, platelets aggregation/activation, skeletal muscleatrophy/hypertrophy, leukocyte recruitment in cancer tissue,angiogenesis, invasion metastisis, in particular melanoma, Karposi'ssarcoma, acute and chronic bacterial and viral infections, sepsis,transplantation complications due to rejection reactions, graftrejection, glomerulo sclerosis, glomerulo nephritis, progressive renalfibrosis, endothelial and epithelial injuries in the lung or in generallung airways inflammation.

The substituents within formula (I) are defined as follows:

A is an unsubstituted or substituted 5-8 membered heterocyclic group oran unsubstituted or substituted carbocyclic group.

Said carbocyclic group may be fused with an unsubstituted or substitutedaryl, an unsubstituted or substituted heteroaryl, an unsubstituted orsubstituted cycloalkyl or an unsubstituted or substitutedheterocycloalkyl.

Such heterocyclic or carbocyclic groups comprise aryl, heteroaryl,cycloalkyl and heterocycloalkyl, including phenyl, phenantrenyl,cyclopentyl, cyclohexyl, norbornyl, pyrrolidine, piperidine, piperazine,1-methylpiperazine, morpholine, pyrrolyl, furanyl, thienyl, imidazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl,benzofuryl, [2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl,benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl,benzimidazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxazolyl,quinolizinyl, quinazolinyl, pthalazinyl, quinoxalinyl, cinnolinyl,napthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl,pyrido[4,3-b]pyridyl, quinolyl, isoquinolyl, tetrazolyl,5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl,pteridinyl, carbazolyl, xantbenyl or benzoquinolyl

Further exemplary heterocyclic or carbocyclic groups A includeunsubstituted or substituted dioxol, unsubstituted or substituteddioxin, unsubstituted or substituted dihydrofuran, unsubstituted orsubstituted (dihydro) furanyl, unsubstituted or substituted(dihydro)oxazinyl, unsubstituted or substituted oxazinoyl, unsubstitutedor substituted pyridinyl, unsubstituted or substituted isooxazolyl,unsubstituted or substituted oxazolyl unsubstituted or substituted(dihydro)napthalenyl, unsubstituted or substituted pyrimidinyl,unsubstituted or substituted triazolyl, unsubstituted or substitutedimidazolyl, unsubstituted or substituted pyrazinyl, unsubstituted orsubstituted thiazolyl, unsubstituted or substituted thiadiazolyl,unsubstituted or substituted oxadiazolyl.

X is S, O or NH, preferably S.

Y¹ and Y² are independently from each other selected from the groupconsisting of S, O or —NH, preferably O.

Z is S or O, preferably O.

R¹ is selected from the group comprising or consisting of H, CN,carboxy, acyl, C₁-C₆-alkoxy, halogen, hydroxy, acyloxy, an unsubstitutedor substituted C₁-C₆-alkyl carboxy, an unsubstituted or substitutedC₁-C₆-alkyl acyloxy, an unsubstituted or substituted C₁-C₆-alkyl alkoxy,alkoxycarbonyl, an unsubstituted or substituted C₁-C₆-alkylalkoxycarbonyl, aminocarbonyl, an unsubstituted or substitutedC₁-C₆-alkyl aminocarbonyl, acylamino, an unsubstituted or substitutedC₁-C₆-alkyl acylamino, ureido, an unsubstituted or substitutedC₁-C₆-alkyl ureido, amino, an unsubstituted or substituted C₁-C₆-alkylamino, ammonium, sulfonyloxy, an unsubstituted or substitutedC₁-C₆-alkyl sulfonyloxy, sulfonyl, an unsubstituted or substitutedC₁-C₆-alkyl sulfonyl, sulfinyl, an unsubstituted or substitutedC₁-C₆-alkyl sulfinyl, sulfanyl, an unsubstituted or substitutedC₁-C₆-alkyl sulfanyl, sulfonylamino, an unsubstituted or substitutedC₁-C₆-alkyl sulfonylamino or carbamate. In a specific embodiment R¹ isH.

R² is selected from the group comprising or consisting of H, halogen,acyl, amino, an unsubstituted or substituted C₁-C₆-alkyl, anunsubstituted or substituted C₂-C₆-alkenyl, an unsubstituted orsubstituted C₂-C₆-alkynyl, an unsubstituted or substituted C₁-C₆-alkylcarboxy, an unsubstituted or substituted C₁-C₆-alkyl acyl, anunsubstituted or substituted C₁-C₆-alkyl alkoxycarbonyl, anunsubstituted or substituted C₁-C₆-alkyl aminocarbonyl, an unsubstitutedor substituted C₁-C₆-alkyl acyloxy, an unsubstituted or substitutedC₁-C₆-alkyl acylamino, an unsubstituted or substituted C₁-C₆-alkylureido, an unsubstituted or substituted C₁-C₆-alkyl carbamate, anunsubstituted or substituted C₁-C₆-alkyl amino, an unsubstituted orsubstituted C₁-C₆-alkyl alkoxy, an unsubstituted or substitutedC₁-C₆-alkyl sulfanyl, an unsubstituted or substituted C₁-C₆-alkylsulfinyl, an unsubstituted or substituted C₁-C₆-alkyl sulfonyl, anunsubstituted or substituted C₁-C₆-alkyl sulfonylaminoaryl, anunsubstituted or substituted aryl, an unsubstituted or substitutedC₃-C₈-cycloalkyl or heterocycloalkyl, an unsubstituted or substitutedC₁-C₆-alkyl aryl, an unsubstituted or substituted C₂-C₆-alkenyl aryl, anunsubstituted or substituted C₂-C₆-alkynyl aryl, carboxy, cyano,hydroxy, C₁-C₆-alkoxy, nitro, acylamino, ureido, sulfonylamino,sulfanyl, or sulfonyl.

n is an integer 0, 1 or 2, preferably n is 0 or 1. Most preferred isn=0.

According to a specific embodiment of the invention, R¹ and R² are bothH.

In a further specific embodiment according to the invention, X is S, Y¹and Y² are both O, R¹ and R² are as above defined and n is 0.

A further particularly preferred aspect of the present invention isrelated to the use of thiazolidinedione-vinyl fused-benzene derivativesof formula (Ia), (Ib), (Ic) and (Id) for the preparation of a medicamentfor the prophylaxis and/or treatment of autoimmune disorders and/orinflammatory diseases, cardiovascular diseases, neurodegenerativediseases, bacterial or viral infections, kidney diseases, plateletaggregation, cancer, transplantation complications due to rejectionreactions, graft rejection or lung injuries

R¹, R², Y¹, Z and n in formula (Ia) are as above-defined.

G in formula (Ia) is an unsubstituted or substituted C₁-C₅ alkylene(e.g. methylene, ethylene, propylene etc.) or an unsubstituted orsubstituted C₁-C₅ alkenylene group (e.g. a methine (—CH═), a —CH═CH—group, a propenylene group, etc.).

W and V in formula (Ia) are each independently from each other selectedfrom O, S, —NR³ wherein R³ is H or an unsubstituted or substituted C₁-C₆alkyl group, m and o are each independently from each other 0 or 1; o isan integer from 1 to 4 and q is an integer from 0 to 4.

Even more preferred compounds of formula (Ia) is where G is an C₁-C₄alkylene, thus giving compounds of formula (Ib) (i.e. p=1, 2, 3 or 4,preferably 1 or 2).

A specific sub-group of formula (Ib) are compounds having the formula(Ic), whereby W, R¹, Y¹ are as above defined; specifically R¹ may be anunsubstituted or substituted C₁-C₄ alkyl group or an unsubstituted orsubstituted C₁-C₅ alkenyl group, carboxy, cyano, C₁-C₄-alkoxy, nitro,acylamino, ureido.

Still a further specific sub-group of formula (Ia) are compounds,wherein V, W and Y¹ are all O, thus providing compounds of formula (Id).

In a preferred embodiment of formulae (Ia), (Ib) or (Id), n is 0, m is1, p is 1 or 2, o is 0, q is 1, and R¹ and R² are as above-defined.

In a further specific embodiment of formulae (Ia), (Ib) or (Id), m is 1,n is 0, p is 1 or 2, q is 0, o is 1 while R¹ and R² are asabove-defined, more particularly R¹ is halogen or a hydrogen atom.

In another specific embodiment of formula (Ia), (Ib) or (Id), p is 1 or2, q is 0, m is 0, n is 1 and R¹ and R² are as above-defined.

The compounds of the present invention are suitable for the modulation,notably the inhibition of the activity of phosphatoinositides 3-kinases(PI3K), particularly phosphatoinositides 3-kinase (PI3Kγ). It istherefore believed that the compounds of the present invention are alsoparticularly useful for the treatment and/or prevention of disorderswhich are mediated by PI3Ks, particularly PI3Kγ. Said treatment involvesthe modulation—notably the inhibition or the down regulation—of thephosphatoinositides 3-kinases.

The following compounds are not included by formula (I):

R¹ is a lower alkyl or aralkyl and R² is H or a halogen. The compoundsTE are disclosed in JP 55 045648 as intermediate compounds without anybiological activity, while JA is mentioned in the Journal of MedicinalChemistry (1998), 41(18), 3515-3529 as being inactive in a paw swellingassay.

Compounds of the present invention include in particular those of thegroup consisting of:

-   5-(1,3-benzodioxol-5-ylmethylene)-1,3-thiazolidine-2,4-dione-   5-(1,3-benzodioxol-5-ylmethylene)-2-thioxo-1,3-thiazolidin-4-one-   5-(2,3-dihydro-1,4-benzodioxin-6-ylmethylene)-1,3-thiazolidine-2,4-dione-   5-(2,3-dihydro-1-benzofuran-5-ylmethylene)-1,3-thiazolidine-2,4-dione-   5-[(7-methoxy-1,3-benzodioxol-5-yl)methylene]-1,3-thiazolidine-2,4-dione-   5-[(9,10-dioxo-9,10-dihydroanthracen-2-yl)methylene]-1,3-thiazolidine-2,4-dione-   (5-[(2,2-difluoro-1,3-benzodioxol-5-yl)methylene]-1,3-thiazolidine-2,4-dione-   (5Z)-5-(1,3-dihydro-2-benzofuran-5-ylmethylene)-1,3-thiazolidine-2,4-dione-   5-(1-benzofuran-5-ylmethylene)-1,3-thiazolidine-2,4-dione-   5-[(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)methylene]-1,3-thiazolidine-2,4-dione-   5-(1,3-benzodioxol-5-ylmethylene)-2-imino-1,3-thiazolidin-4-one-   5-Quinolin-6-ylmethylene-thiazolidine-2,4-dione-   5-Quinolin-6-ylmethylene-2-thioxo-thiazolidin-4-one-   2-Imino-5-quinolin-6-ylmethylene-thiazolidin-4-one-   5-(3-Methyl-benzo[d]isoxazol-5-ylmethylene)-thiazolidine-2,4-dione-   5-(4-Phenyl-quinazolin-6-ylmethylene)-thiazolidine-2,4-dione-   5-(4-Dimethylamino-quinazolin-6-ylmethylene)-thiazolidine-2,4-dione-   5-[(4-aminoquinazolin-6-yl)methylene]-1,3-thiazolidine-2,4-dione-   5-[(4-piperidin-1-ylquinazolin-6-yl)methylene]-1,3-thiazolidine-2,4-dione-   5-[(4-morpholin-4-ylquinazolin-6-yl)methylene]-1,3-thiazolidine-2,4-dione-   5-{[4-(benzylamino)quinazolin-6-yl]methylene}-1,3-thiazolidine-2,4-dione-   5-{[4-(diethylamino)quinazolin-6-yl]methylene}-1,3-thiazolidine-2,4-dione-   5-({4-[(pyridin-2-ylmethyl)amino]quinazolin-6-yl}methylene)-1,3-thiazolidine-2,4-dione-   5-({4-[(pyridin-3-ylmethyl)amino]quinazolin-6-yl}methylene)-1,3-thiazolidine-2,4-dione-   ethyl    1-{6-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]quinazolin-4-yl}piperidine-3-carboxylate-   ethyl    1-{6-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]quinazolin-4-yl}piperidine-4-carboxylate-   tert-butyl    1-{6-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]quinazolin-4-yl}-L-prolinate-   5-{[4-(4-methylpiperazin-1-yl)quinazolin-6-yl]methylene}-1,3-thiazolidine-2,4-dione-   5-{[4-(4-pyrimidin-2-ylpiperazin-1-yl)quinazolin-6-yl]methylene}-1,3-thiazolidine-2,4-dione-   5-({4-[4-(4-fluorophenyl)piperidin-1-yl]quinazolin-6-yl}methylene)-1,3-thiazolidine-2,4-dione-   5-{[4-(4-benzylpiperidin-1-yl)quinazolin-6-yl]methylene}-1,3-thiazolidine-2,4-dione-   5-({4-[4-(2-phenylethyl)piperidin-1-yl]quinazolin-6-yl}methylene)-1,3-thiazolidine-2,4-dione-   5-{[4-(4-methylpiperidin-1-yl)quinazolin-6-yl]methylene}-1,3-thiazolidine-2,4-dione-   5-{[4-(4-hydroxypiperidin-1-yl)quinazolin-6-yl]methylene}-1,3-thiazolidine-2,4-dione-   1-[6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-quinazolin-4-yl]-piperidine-4-carboxylic    acid-   1-[6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-quinazolin-4-yl]-piperidine-3-carboxylic    acid-   1-[6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-quinazolin-4-yl]-pyrrolidine-2-carboxylic    acid-   5-(4-Methylamino-quinazolin-6-ylmethylene)-thiazolidine-2,4-dione-   5-(4-Methoxy-quinazolin-6-ylmethylene)-thiazolidine-2,4-dione-   2-Imino-5-(4-methylamino-quinazolin-6-ylmethylene)-thiazolidin-4-one-   2-Imino-5-(4-piperidine-quinazolin-6-ylmethylene)-thiazolidin-4-one-   2-Imino-5-(4-dimethylamino-quinazolin-6-ylmethylene)-thiazolidin-4-one-   5-(2-Methyl-2H-benzotriazol-5-ylmethylene)-thiazolidine-2,4-dione-   5-(3-Methyl-3H-benzotriazol-5-ylmethylene)-thiazolidine-2,4-dione-   5-(3-Ethyl-3H-benzoimidazol-5-ylmethylene)-thiazolidine-2,4-dione-   5-{[1-(4-phenylbutyl)-1H-benzimidazol-6-yl]methylene}-1,3-thiazolidine-2,4-dione-   5-[(1-prop-2-yn-1-yl-1H-benzimidazol-6-yl)methylene]-1,3-thiazolidine-2,4-dione-   5-[(1-{2-[4-(trifluoromethyl)phenyl]ethyl}-1H-benzimidazol-6-yl)methylene]-1,3-thiazolidine-2,4-dione-   5-({1-[2-(4-hydroxyphenyl)ethyl]-1H-benzimidazol-6-yl}methylene)-1,3-thiazolidine-2,4-dione-   methyl    4-{6-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1H-benzimidazol-1-yl}cyclohexanecarboxylate-   5-({1-[2-(5-methoxy-1H-indol-3-yl)ethyl]-1H-benzimidazol-6-yl}methylene)-1,3-thiazolidine-2,4-dione-   5-({1-[(1-methyl-1H-pyrazol-4-yl)methyl]-1H-benzimidazol-6-yl}methylene)-1,3-thiazolidine-2,4-dione-   5-({1-[2-(3,4-dimethoxyphenyl)ethyl]-1H-benzimidazol-6-yl}methylene)-1,3-thiazolidine-2,4-dione-   5-({1-[2-(4-phenoxyphenyl)ethyl]-1H-benzimidazol-6-yl}methylene)-1,3-thiazolidine-2,4-dione-   5-({1-[4-(trifluoromethyl)benzyl]-1H-benzimidazol-6-yl}methylene)-1,3-thiazolidine-2,4-dione-   4-{6-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1H-benzimidazol-1-yl}cyclohexanecarboxylic    acid-   5-[(1-isobutyl-1H-benzimidazol-6-yl)methylene]-1,3-thiazolidine-2,4-dione-   5-({1-[2-(1,3-benzodioxol-4-yl)ethyl]-1H-benzimidazol-6-yl}methylene)-1,3-thiazolidine-2,4-dione-   5-({1-[2-(2-phenoxyphenyl)ethyl]-1H-benzimidazol-6-yl}methylene)-1,3-thiazolidine-2,4-dione-   5-{[1-(3,3-diphenylpropyl)-1H-benzimidazol-6-yl]methylene}-1,3-thiazolidine-2,4-dione-   5-{[1-(2-methoxybenzyl)-1H-benzimidazol-6-yl]methylene}-1,3-thiazolidine-2,4-dione-   5-{[1-(3-furylmethyl)-1H-benzimidazol-6-yl]methylene}-1,3-thiazolidine-2,4-dione-   5-[(1-propyl-1H-benzimidazol-6-yl)methylene]-1,3-thiazolidine-2,4-dione-   5-Quinoxalin-6-ylmethylene-thiazolidine-2,4-dione-   5-Quinoxalin-6-ylmethylene-2-thioxo-thiazolidin-4-one-   2-Imino-5-quinoxalin-6-ylmethylene-thiazolidin-4-one-   5-Benzothiazol-6-ylmethylene-thiazolidine-2,4-dione-   5-(3-Methyl-benzofuran-5-ylmethylene)-thiazolidine-2,4-dione-   5-(2-Bromo-3-methyl-benzofuran-5-ylmethylene)-thiazolidine-2,4-dione-   5-(3-bromo-benzofuran-5-ylmethylene)-thiazolidine-2,4-dione-   3-[5-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-benzofuran-3-yl]-acrylic    acid ethyl ester-   3-[5-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-benzofuran-3-yl]-acrylic    acid-   5-[3-(3-Oxo-3-piperidin-1-yl-propenyl)-benzofuran-5-ylmethylene]-thiazolidine-2,4-dione-   Methyl    1-((3-{5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1-benzofuran-3-yl}prop-2-enoyl)prolinate-   Methyl    1-((3-{5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1-benzofuran-3-yl}prop-2-enoyl)-D-prolinate-   (5-({3-[(3-oxo-3-pyrrolidin-1-ylprop-1-en-1-yl]-1-benzofuran-5-yl}methylene)-1,3-thiazolidine-2,4-dione-   5-({3-[3-morpholin-4-yl-3-oxoprop-1-en-1-yl]-1-benzofuran-5-yl}methylene)-1,3-thiazolidine-2,4-dione-   Methyl    1-(3-{5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1-benzofuran-3-yl}prop-2-enoyl)-L-prolinate-   N-cyclohexyl-3-{5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1-benzofuran-3-yl}-N-methylacrylamide-   3-{5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1-benzofuran-3-yl}-N-ethyl-N-(2-hydroxyethyl)acrylamide-   N-cyclobutyl-3-{5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1-benzofuran-3-yl}acrylamide-   5-({3-[3-azetidin-1-yl-3-oxoprop-1-en-1-yl]-1-benzofuran-5-yl}methylene)-1,3-thiazolidine-2,4-dione-   5-({3-[3-(1,3-dihydro-2H-isoindol-2-yl)-3-oxoprop-1-en-1-yl]-1-benzofuran-5-yl}methylene)-1,3-thiazolidine-2,4-dione-   5-({3-[3-azepan-1-yl-3-oxoprop-1-en-1-yl]-1-benzofuran-5-yl}methylene)-1,3-thiazolidine-2,4-dione-   3-{5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1-benzofuran-3-yl}-N-piperidin-1-ylacrylamide-   3-{5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1-benzofuran-3-yl}-N-(pyridin-3-ylmethyl)acrylamide-   N-cyclohexyl-3-{5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1-benzofuran-3-yl}acrylamide-   5-({3-[3-(4-methylpiperazin-1-yl)-3-oxoprop-1-en-1-yl]-1-benzofuran-5-yl}methylene)-1,3-thiazolidine-2,4-dione-   N-cycloheptyl-3-{5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1-benzofuran-3-yl}acrylamide-   5-({3-[3-(2,5-dihydro-1H-pyrrol-1-yl)-3-oxoprop-1-en-1-yl]-1-benzofuran-5-yl}methylene)-1,3-thiazolidine-2,4-dione-   N-cyclopentyl-3-{5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1-benzofuran-3-yl}acrylamide-   3-[5-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-benzofuran-3-yl]-propionic    acid ethyl ester-   3-[5-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-benzofuran-3-yl]-propionic    acid-   5-[3-(3-Oxo-3-piperidin-1-yl-propyl)-benzofuran-5-ylmethylene]-thiazolidine-2,4-dione-   6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic    acid tert-butyl ester-   5-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethylene)-thiazolidine-2,4-dione-   5-(4-Benzoyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethylene)-thiazolidine-2,4-dione-   5-(4-Acetyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethylene)-thiazolidine-2,4-dione-   6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-benzo[1,4]oxazine-4-carboxylic    acid tert-butyl ester-   [6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-3-oxo-2,3-dihydro-benzo[1,4]-oxazin-4-yl]-acetic    acid methyl ester-   N-Benzyl-2-[6-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl]-acetamide-   5-(4-Butyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethylene)-thiazolidine-2,4-dione-   5-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethylene)-thiazolidine-2,4-dione-   5-(2-Chloro-benzofuran-5-ylmethylene)-thiazolidine-2,4-dione-   5-(3-Amino-benzo[d]isoxazol-5-ylmethylene)-thiazolidine-2,4-dione-   5-(3-Phenylethynyl-benzofuran-5-ylmethylene)-thiazolidine-2,4-dione-   5-Benzo[1,2,5]thiadiazol-5-ylmethylene-thiazolidine-2,4-dione-   5-Benzo[1,2,5]oxadiazol-5-ylmethylene-thiazolidine-2,4-dione-   5-(2-Methyl-benzofuran-6-ylmethylene)-thiazolidine-2,4-dione-   5-(2-Carboxymethyl-benzofuran-6-ylmethylene)-thiazolidine-2,4-dione-   5-(3-Bromo-2-fluoro-2,3-dihydro-benzofuran-6-ylmethylene)-thiazolidine-2,4-dione-   5-(2-Fluoro-benzofuran-6-ylmethylene)-thiazolidine-2,4-dione

A further aspect of the invention consists in novelthiazolidinedione-vinyl fused-benzene derivatives of formula (II-a)

A is selected from the group consisting of unsubstituted or substituteddioxol, unsubstituted or substituted dioxin, unsubstituted orsubstituted dihydrofuran, unsubstituted or substituted (dihydro)furanyl, unsubstituted or substituted (dihydro)oxazinyl, unsubstitutedor substituted oxazinoyl, unsubstituted or substituted pyridinyl,unsubstituted or substituted isooxazolyl, unsubstituted or substitutedoxazolyl unsubstituted or substituted (dihydro)napthalenyl,unsubstituted or substituted pyrimidinyl, unsubstituted or substitutedtriazolyl, unsubstituted or substituted imidazolyl, unsubstituted orsubstituted pyrazinyl, unsubstituted or substituted thiazolyl,unsubstituted or substituted thiadiazolyl, unsubstituted or substitutedoxadiazolyl.

R² is selected from the group comprising or consisting of H, halogen,acyl, amino, unsubstituted or substituted C₁-C₆-alkyl, unsubstituted orsubstituted C₂-C₆-alkenyl, unsubstituted or substituted C₂-C₆-alkynyl,unsubstituted or substituted C₁-C₆-alkyl carboxy, unsubstituted orsubstituted C₁-C₆-alkyl acyl, unsubstituted or substituted C₁-C₆-alkylalkoxycarbonyl, unsubstituted or substituted C₁-C₆-alkyl aminocarbonyl,unsubstituted or substituted C₁-C₆-alkyl acyloxy, unsubstituted orsubstituted C₁-C₆-alkyl acylamino, unsubstituted or substitutedC₁-C₆-alkyl ureido, unsubstituted or substituted C₁-C₆-alkyl carbamate,unsubstituted or substituted C₁-C₆-alkyl amino, unsubstituted orsubstituted C₁-C₆-alkyl alkoxy, unsubstituted or substituted C₁-C₆-alkylsulfanyl, unsubstituted or substituted C₁-C₆-alkyl sulfinyl,unsubstituted or substituted C₁-C₆-alkyl sulfonyl, unsubstituted orsubstituted C₁-C₆-alkyl sulfonylaminoaryl, an unsubstituted orsubstituted aryl, unsubstituted or substituted C₃-C₈-cycloalkyl orheterocycloalkyl, unsubstituted or substituted C₁-C₆-alkyl aryl,unsubstituted or substituted C₂-C₆-alkenyl-aryl, unsubstituted orsubstituted C₂-C₆-alkynyl aryl, carboxy, cyano, hydroxy, C₁-C₆-alkoxy,nitro, acylamino, ureido, sulfonylamino, sulfanyl, or sulfonyl.

More specific novel thiazolidinone-vinyl fused-benzene derivatives offormula (II)

as well as its geometrical isomers, its optically active forms asenantiomers, diastereomers and its racemate forms, as well aspharmaceutically acceptable salts and pharmaceutically activederivatives thereof, wherein Y¹, Z, R¹, R² are as above defined and n is0 or 1.

In a specific embodiment R¹ is an unsubstituted or substitutedC₁-C₆-alkyl, an unsubstituted or substituted C₁-C₆-alkyl aryl, anunsubstituted or substituted aryl, an unsubstituted or substitutedC₃-C₈-cycloalkyl or -heterocycloalkyl, an unsubstituted or substitutedC₁-C₆-alkyl aryl, an unsubstituted or substituted C₂-C₆-alkenyl-aryl, anunsubstituted or substituted C₂-C₆-alkynyl aryl.

In another preferred embodiment according to the present invention Y¹ isO.

Still another aspect of the invention consists in novelthiazolidinone-vinyl fused-benzene derivatives of formula (III)

as well as its geometrical isomers, its optically active forms asenantiomers, diastereomers and its racemate forms, as well aspharmaceutically acceptable salts and pharmaceutically activederivatives thereof, wherein R¹ and R² are as above defined (the dottedline represents the optional presence of a double bond).

Still a further embodiment comprises compounds of formulae (IV), (V) and(VI):

R¹ is selected from the group consisting of hydrogen, halogen, cyano,C₁-C₆-alkyl, C₁-C₆-alkoxy, acyl, alkoxy cabonyl, while R² is as abovedefined. In a specific embodiment R² is an amino moiety.

A further aspect of the present invention is the use of the novelcompounds of formulae (II), (II-a), (III), (IV), (V) or (VI) asmedicament.

Another further aspect of the invention is a pharmaceutical compositioncontaining at least one thiazolidinone-vinyl fused-benzene derivativeaccording to formulae (II), (III), (IV), (V) or (VI) and apharmaceutically acceptable carrier, diluent or excipient thereof.

Still a further aspect of the invention is the use of compoundsaccording to formula (II), (III), (IV), (V) or (VI) for the preparationof a medicament for the prophylaxis and/or treatment of diseasesmediated by a PI3 Kinase, particularly PI3 Kinase γ.

Specific diseases are the ones selected in the group comprising orconsisting of autoimmune disorders and/or inflammatory diseases,cardiovascular diseases, neurodegenerative diseases, bacterial or viralinfections, kidney diseases, platelet aggregation, cancer,transplantation complications due to rejection reactions, graftrejection or lung injuries.

In a preferred embodiment, said compounds are useful for the treatmentand/or prophylaxis of autoimmune diseases or inflammatory diseases suchas multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupuserythematosis, inflammatory bowel disease, lung inflammation, thrombosisor brain infection/inflammation such as meningitis or encephalitis.

In another preferred embodiment according to the invention, thesecompounds are useful for the treatment and/or prophylaxis ofneurodegenerative diseases including multiple sclerosis, Alzheimer'sdisease, Huntington's disease, CNS trauma, stroke or ischemicconditions.

In a particularly preferred embodiment according to the invention, thesecompounds are useful for the treatment and/or prophylaxis ofcardiovascular diseases such as atherosclerosis, heart hypertrophy,cardiac myocyte dysfunction, elevated blood pressure orvasoconstriction.

In another particularly preferred embodiment according to the invention,these compounds are useful for the treatment and/or prophylaxis ofchronic obstructive pulmonary disease, anaphylactic shock fibrosis,psoriasis, allergic diseases, asthma, stroke or ischemic conditions,ischemia-reperfusion, platelets aggregation/activation, skeletal muscleatrophy/hypertrophy, leukocyte recruitment in cancer tissue,angiogenesis, invasion metastisis, in particular melanoma, Karposi'ssarcoma, acute and chronic bacterial and viral infections, sepsis,transplantation complications due to rejection reactions, graftrejection, glomerulo sclerosis, glomerulo nephritis, progressive renalfibrosis, endothelial and epithelial injuries in the lung or in generallung airways inflammation.

According to the present invention, compounds of formula (II), (II-a),(III) (IV), (V) or (VI) are suitable to modulate, particularly toinhibit, PI3 kinase activity and more particularly PI3Kγ activity.

Still a further object of the present invention is a process forpreparing azolidinone-vinyl fused-benzene derivatives according toformula (I), (Ia), (Ib), (Ic) or (Id) but also thiazolidinone-vinylfused-benzene derivatives of formulae (II), (II-a), (III), (IV), (V) or(VI).

The azolidinone-vinyl fused-benzene derivatives exemplified in thisinvention may be prepared from readily available starting materialsusing the following general methods and procedures. It will beappreciated that where typical or preferred experimental conditions(i.e. reaction temperatures, time, moles of reagents, solvents etc.) aregiven, other experimental conditions can also be used unless otherwisestated. Optimum reaction conditions may vary with the particularreactants or solvents used, but such conditions can be determined by theperson skilled in the art, using routine optimisation procedures.

In the process illustrated in the following schemes R¹, R², G, V, W, Y¹,Y², Z, m, n, o, p and q are each as above-defined in the description.

Generally, the azolidinone-vinyl fused-benzene derivatives according tothe general formula (I) could be obtained by several syntheticapproaches, using both solution-phase and solid-phase chemistryprotocols (Brummond et. al., J.O.C., 64, 1723-1726 (1999)), either byconventional methods or by microwave-assisted techniques.

In a first step, approximately equimolar amounts of the aldehydereactant P1 (P1a) and compound 2 (in particular thiazolidinedione orrhodanin P3) are heated in the presence of a preferably mild base toprovide the corresponding olefin of formula (Ia). In the first step, P1amay be replaced by precursors P1b and P1c in order to obtain the finalcompounds (Ib) and (Ic) respectively as above described in thedescription.

Particularly preferred process according to the invention areillustrated by the following schemes 3 and 4 in which compounds offormula (II) and (III) respectively, may be obtained using the samereaction as above-mentioned.

While this step may be carried out in the absence of a solvent at atemperature, which is sufficiently high to cause at least partialmelting of the reaction mixture, it is preferably carried out in thepresence of a inert solvent. A preferred temperature range is from about100° C. to 250° C., and especially preferred is a temperature of fromabout 120° C. to 200° C. Examples of such solvents for the abovereaction include solvents like dimethoxymethane, xylene, toluene,o-dichlorobenzene etc. Examples of suitable mild bases for the abovereaction are alkali metal and alkaline earth salts of week acids such asthe (C₁-C₁₂)-alkyl carboxylic acids and benzoic acid, alkali metal andalkaline earth carbonates and bicarbonates such as calcium carbonate,magnesium carbonate, potassium bicarbonate and secondary amines such aspiperidine, morpholine as well as tertiary amines such as pyridine,triethylamine, diisopropylethylamine, N-methylmorpholine,N-ethylpiperidine, N-methylpiperidine and the like. Especially preferredmild bases are sodium acetate or piperidine for reasons of economy andefficiency.

In a typical such reaction (Tietze et. al., in “The Knoevenagelreaction”, p. 341 ff., Pergamon Press, Oxford 1991, Eds.: Trost B. M.,Fleming I.) the aldehyde starting material P1a and the other startingcompound (e.g. thiazolidinedione) P3 are combined in approximatelyequimolar amounts with 0.5 to one equivalent of piperidine indimethoxymethane or similar solvent and heated between 120 and 200° C.at which the reaction is substantially complete in from about 15 minutesto 3 hours. The desired olefin of formula (Ia) is then isolated byfiltration, in case it precipitated out of the reaction mixture uponcooling, or for example, by mixing with water and subsequent filtration,to obtain the crude product, which is purified, if desired, e.g. bycrystallization or by standard chromatographic methods.

Alternatively compounds of formula (Ia) may be obtained typically bymixing equimolar amounts of thiazolidinedione P3 with aldehyde P1a andmolar excess, preferably a 2-4 fold excess, of anhydrous sodium acetateand the mixture is heated at a temperature high enough to effectmelting, at which temperature the reaction is mainly complete in from 5to 60 minutes.

Preferably the above reaction is carried out in acidic media such asacetic acid in the presence of sodium acetate or beta-alanine.

Above described reactions may be carried out alternatively undermicrowave conditions as heating source. Typically the aldehyde startingmaterial P1a and thiazolidinedione P3 are combined in approximatelyequimolar amounts with 0.5 to one equivalent of piperidine indimethoxymethane or similar solvent and heated between 140° C. and 240°C. at which the reaction is substantially complete in from 3 to 10minutes.

The pharmaceutically acceptable cationic salts of compounds of thepresent invention are readily prepared by reacting the acid forms withan appropriate base, usually one equivalent, in a co-solvent. Typicalbases are sodium hydroxide, sodium methoxide, sodium ethoxide, sodiumhydride, potassium hydroxide, potassium methoxide, magnesium hydroxide,calcium hydroxide, benzathine, choline, diethanolamine, ethylenediamine,meglumine, benethamine, diethylamine, piperazine and tromethamine. Thesalt is isolated by concentration to dryness or by addition of anon-solvent. In some cases, salts can be prepared by mixing a solutionof the acid with a solution of the cation (sodium ethylhexanoate,magnesium oleate), employing a solvent in which the desired cationicsalt precipitates, or can be otherwise isolated by concentration andaddition of a non-solvent.

2,4-Azolidinone derivatives P3 are commercially available from varioussources. The aldehydes of formula PI a are prepared by a variety of wellknown methods, for example starting from the corresponding carboxylicacid alkyl ester or carboxylic acid by oxido-reduction, using standardtechniques to reduce carboxylic acid alkyl ester or carboxylic acid tobenzylic alcohols with lithium aluminium hydride, diisopropylaluminumetc. and ultimately re-oxidize the corresponding benzylic alcohol to thecorresponding aldehyde by mild oxidation with reagents such as manganesedioxide, chromic acid, Dess-Martin reagent or Swern oxidation, or underconditions known to produce aldehydes from primary alcohols. Analternative way may be the direct reduction of the correspondingcarboxylic acid alkyl ester or carboxylic acid to the correspondingaldehyde, using DIBAL at low temperature or any other techniques knownin the field.

An alternative way to prepare the appropriate aldehydes is the selectivereduction of a nitrile moiety to the corresponding aldehyde using knownmethods like e.g. DIBAL etc. Another way to access aldehydes of formulaP1a is the selective reduction of the corresponding acyl chloride usinge.g. Lithiumaluminium-tri-tert-butoxyhydride (Cha J. S., Brown H. C.,J.O.C 1993, 58, p. 4732-34). Another alternative way to produce theappropriate aldehydes is the reaction of the corresponding benzenederivative in a Friedl-Crafts type of reaction wherein the substrate P4as shown in the above scheme 5 is reacted with 1,1-dichloromethylmethylether in the presence of a Lewis acid such as titanium tetrachloride oraluminium trichloride or any corresponding Lewis acids suitable for suchtype of reaction.

According to a more particularly preferred process of the invention, asdescribed in the literature (Petrov O. I., Kalcheva V. B., Antonova A.T., Collect. Czech. Chem. Commun, 62, p. 494-7 (1997)) and illustratedby Scheme 6 hereinafter, reactant P2 may be obtained starting from P5 byreacting with 1,1-dichloromethylmethyl ether as above-described.

According to another more particularly preferred process of theinvention, as illustrated by Scheme 7 hereinafter, reactant P6 may beobtained starting from P7 by reacting with DMF and the presence ofmagnesium or n-butyl-lithium or any other method known to the personskilled in the art.

According to another more particularly preferred process of theinvention, as illustrated by Scheme 8 hereinafter, reactant P6 may beobtained starting from P9 by reacting n-butyllithium or LDA in thepresence of an appropriate electrophile R¹—-X, or any other method knownto the person skilled in the art. This method may be repeated for P8 inorder to obtain P6 accordingly.

Similarly, saturated precursors P6 may be obtained in a one-pot reactionusing P9 and appropriate electrophiles R¹—X and R²—X as set out inScheme 9.

If the above set out general synthetic methods are not applicable toobtain compounds according to formula (I) and/or to necessaryintermediates for the synthesis of compounds of formula (I), suitablemethods of preparation known by a person skilled in the art should beused. In general, the synthesis pathways for any individual compound offormula (I) will depend on the specific substitutents of each moleculeand upon the ready availability of intermediates necessary; again suchfactors being appreciated by those of ordinary skill in the art.

For all the protection and deprotection methods, see Philip J.Kocienski, in “Protecting Groups”, Georg Thieme Verlag Stuttgart NewYork, 1994 and, Theodora W. Greene and Peter G. M. Wuts in “ProtectiveGroups in Organic Synthesis”, Wiley Interscience, 3^(rd) Edition 1999.

Compounds of this invention can be isolated in association with solventmolecules by crystallization from evaporation of an appropriate solvent.The pharmaceutically acceptable acid addition salts of the compounds ofthe present invention which contain a basic center, may be prepared in aconventional manner. For example, a solution of the free base may betreated with a suitable acid, either neat or in a suitable solution, andthe resulting salt isolated either by filtration or by evaporation undervacuum of the reaction solvent. Pharmaceutically acceptable baseaddition salts may be obtained in an analogous manner by treating asolution of compound of the present invention with a suitable base. Bothtypes of salts may be formed or interconverted using ion-exchange resintechniques.

When employed as pharmaceuticals, azolidinedione-vinyl fused-benzenederivatives of the present invention are typically administered in theform of a pharmaceutical composition. Hence, pharmaceutical compositionscomprising a compound of the present invention a pharmaceuticallyacceptable carrier, diluent or excipient therefore are also within thescope of the present invention. A person skilled in the art is aware ofa whole variety of such carrier, diluent or excipient compounds suitableto formulate a pharmaceutical composition.

The compounds of the invention, together with a conventionally employedadjuvant, carrier, diluent or excipient may be placed into the form ofpharmaceutical compositions and unit dosages thereof, and in such formmay be employed as solids, such as tablets or filled capsules, orliquids such as solutions, suspensions, emulsions, elixirs, or capsulesfilled with the same, all for oral use, or in the form of sterileinjectable solutions for parenteral (including subcutaneous use). Suchpharmaceutical compositions and unit dosage forms thereof may compriseingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed.

Pharmaceutical compositions containing azolidinedione-vinylfused-benzene derivatives of this invention can be prepared in a mannerwell known in the pharmaceutical art and comprise at least one activecompound. Generally, the compounds of this invention are administered ina pharmaceutically effective amount. The amount of the compound actuallyadministered will typically be determined by a physician, in the lightof the relevant circumstances, including the condition to be treated,the chosen route of administration, the actual compound administered,the age, weight, and response of the individual patient, the severity ofthe patient's symptoms, and the like.

The pharmaceutical compositions of the present invention can beadministered by a variety of routes including oral, rectal, transdermal,subcutaneous, intravenous, intramuscular and intranasal. Thecompositions for oral administration can take the form of bulk liquidsolutions or suspensions, or bulk powders. More commonly, however, thecompositions are presented in unit dosage forms to facilitate accuratedosing. The term “unit dosage forms” refers to physically discrete unitssuitable as unitary dosages for human subjects and other mammals, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect, in association with asuitable pharmaceutical excipient. Typical unit dosage forms includeprefilled, premeasured ampoules or syringes of the liquid compositionsor pills, tablets, capsules or the like in the case of solidcompositions. In such compositions, the thiazolidinedione-vinylfused-benzene derivative is usually a minor component (from about 0.1 toabout 50% by weight or preferably from about 1 to about 40% by weight)with the remainder being various vehicles or carriers and processingaids helpful for forming the desired dosing form.

Liquid forms suitable for oral administration may include a suitableaqueous or nonaqueous vehicle with buffers, suspending and dispensingagents, colorants, flavors and the like. Solid forms may include, forexample, any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatine; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable carriers knownin the art. As above mentioned, the thiazolidinedione-vinylfused-benzene derivatives of formula (I) in such compositions istypically a minor component, frequently ranging between 0.05 to 10% byweight with the remainder being the injectable carrier and the like.

The above described components for orally administered or injectablecompositions are merely representative. Further materials as well asprocessing techniques and the like are set out in Part 5 of Remington'sPharmaceutical Sciences, 20^(th) Edition, 2000, Marck PublishingCompany, Easton, Pa., which is incorporated herein by reference.

The compounds of this invention can also be administered in sustainedrelease forms or from sustained release drug delivery systems. Adescription of representative sustained release materials can also befound in the incorporated materials in Remington's PharmaceuticalSciences.

In the following the present invention shall be illustrated by means ofsome examples which are not construed to be viewed as limiting the scopeof the invention. The following abbreviations are hereinafter used inthe accompanying examples: min (minute), hr (hour), g (gram), mmol(millimole), m.p. (melting point), eq (equivalents), ml (milliliter), μl(microliters), ACN (acetonitrile), Boc (butoxycarbonyl), Cbz(carboxybenzyl), CDCl₃ (deuterated chloroform), cHex (cyclohexane), dba(dibenzylideneacetone), DCM (dichloromethane), DEAD(diethylazodicarboxylate, DIC (diisopropylcarbodiimide), DIEA(diisopropylethylamine), DMAP (4-dimethylaminopyridine), DME(dimethoxyethane), DMF (dimethylformamide), DMSO (dimethylsulfoxide),DMSO-d₆ (deuterated dimethylsulfoxide), EDC(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride), EtOAc(ethylacetate), Et₂O (diethylether), Fmoc (9-fluorenylmethoxy-carbonyl),HOBt (1-hydroxybenzotriazole), K₂CO₃ (potassium carbonate), MgSO₄(magnesium sulfate), MsCl (methylsulfonylchloride), MTBE(tert-butylmethylether), NaH (sodium hydride), NaHCO₃ (sodiumbicarbonate), nBuLi (n-butyllithium), PCC (pyridinium chlorochroinate),PE (petroleum ether), QCl (tetrabutylammonium chloride), rt (roomtemperature), TBTU(O-benzotriazolyl-N,N,N′,N′-tetramethyluronium-tetrafluoroborate), TEA(triethylamine), TFA (trifluoroacetic acid), THF (tetrahydrofuran), TMOF(trimethylorthoformate), TMAD (N,N,N′,N′-tetramethylazodicarboxamide),TosCl (toluenesulfonylchloride).

EXAMPLES

The following list of compounds were synthesized according to the belowmentioned methods:

Example Name 15-(1,3-benzodioxol-5-ylmethylene)-1,3-thiazolidine-2,4-dione 25-(1,3-benzodioxol-5-ylmethylene)-2-thioxo-1,3-thiazolidin-4-one 35-(2,3-dihydro-1,4-benzodioxin-6-ylmethylene)-1,3-thiazolidine-2,4-dione4 5-(2,3-dihydro-1-benzofuran-5-ylmethylene)-1,3-thiazolidine-2,4-dione55-[(7-methoxy-1,3-benzodioxol-5-yl)methylene]-1,3-thiazolidine-2,4-dione65-[(9,10-dioxo-9,10-dihydroanthracen-2-yl)methylene]-1,3-thiazolidine-2,4-dione7(5-[(2,2-difluoro-1,3-benzodioxol-5-yl)methylene]-1,3-thiazolidine-2,4-dione8(5Z)-5-(1,3-dihydro-2-benzofuran-5-ylmethylene)-1,3-thiazolidine-2,4-dione9 5-(1-benzofuran-5-ylmethylene)-1,3-thiazolidine-2,4-dione 105-[(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)methylene]-1,3-thiazolidine-2,4-dione 115-(1,3-benzodioxol-5-ylmethylene)-2-imino-1,3-thiazolidin-4-one 125-Quinolin-6-ylmethylene-thiazolidine-2,4-dione 135-Quinolin-6-ylmethylene-2-thioxo-thiazolidine-4-one 142-Imino-5-quinolin-6-ylmethylene-thiazolidine-4-one 155-(3-Methyl-benzo[d]isoxazol-5-ylmethylene)-thiazolidine-2,4-dione 165-(4-Phenyl-quinazolin-6-ylmethylene)-thiazolidine-2,4-dione 175-(4-Dimethylamino-quinazolin-6-ylmethylene)-thiazolidine-2,4-dione 185-[(4-aminoquinazolin-6-yl)methylene]-1,3-thiazolidine-2,4-dione 195-[(4-piperidin-1-ylquinazolin-6-yl)methylene]-1,3-thiazolidine-2,4-dione205-[(4-morpholin-4-ylquinazolin-6-yl)methylene]-1,3-thiazolidine-2,4-dione215-{[4-(benzylamino)quinazolin-6-yl]methylene}-1,3-thiazolidine-2,4-dione225-{[4-(diethylamino)quinazolin-6-yl]methylene}-1,3-thiazolidine-2,4-dione235-({4-[(pyridin-2-ylmethyl)amino]quinazolin-6-yl}methylene)-1,3-thiazolidine-2,4-dione 245-({4-[(pyridin-3-ylmethyl)amino]quinazolin-6-yl}methylene)-1,3-thiazolidine-2,4-dione 25 ethyl1-{6-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]quinazolin-4-yl}piperidine-3-carboxylate 26 ethyl1-{6-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]quinazolin-4-yl}piperidine-4-carboxylate 27 tert-butyl1-{6-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]quinazolin-4-yl}-L-prolinate 285-{[4-(4-methylpiperazin-1-yl)quinazolin-6-yl]methylene}-1,3-thiazolidine-2,4-dione 295-{[4-(4-pyrimidin-2-ylpiperazin-1-yl)quinazolin-6-yl]methylene}-1,3-thiazolidine-2,4-dione 305-({4-[4-(4-fluorophenyl)piperidin-1-yl]quinazolin-6-yl}methylene)-1,3-thiazolidine-2,4-dione 315-{[4-(4-benzylpiperidin-1-yl)quinazolin-6-yl]methylene}-1,3-thiazolidine-2,4-dione 325-({4-[4-(2-phenylethyl)piperidin-1-yl]quinazolin-6-yl}methylene)-1,3-thiazolidine-2,4-dione 335-{[4-(4-methylpiperidin-1-yl)quinazolin-6-yl]methylene}-1,3-thiazolidine-2,4-dione 345-{[4-(4-hydroxypiperidin-1-yl)quinazolin-6-yl]methylene}-1,3-thiazolidine-2,4-dione 351-[6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-quinazolin-4-yl]-piperidine-4-carboxylic acid 361-[6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-quinazolin-4-yl]-piperidine-3-carboxylic acid 371-[6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-quinazolin-4-yl]-pyrrolidine-2-carboxylic acid 385-(4-Methylamino-quinazolin-6-ylmethylene)-thiazolidine-2,4-dione 395-(4-Methoxy-quinazolin-6-ylmethylene)-thiazolidine-2,4-dione 402-Imino-5-(4-methylamino-quinazolin-6-ylmethylene)-thiazolidin-4-one 412-Imino-5-(4-piperidine-quinazolin-6-ylmethylene)-thiazolidin-4-one 422-Imino-5-(4-dimethylamino-quinazolin-6-ylmethylene)-thiazolidin-4-one43 5-(2-Methyl-2H-benzotriazol-5-ylmethylene)-thiazolidine-2,4-dione 445-(3-Methyl-3H-benzotriazol-5-ylmethylene)-thiazolidine-2,4-dione 455-(3-Ethyl-3H-benzoimidazol-5-ylmethylene)-thiazolidine-2,4-dione 465-{[1-(4-phenylbutyl)-1H-benzimidazol-6-yl]methylene}-1,3-thiazolidine-2,4-dione 475-[(1-prop-2-yn-1-yl-1H-benzimidazol-6-yl)methylene]-1,3-thiazolidine-2,4-dione485-[(1-{2-[4-(trifluoromethyl)phenyl]ethyl}-1H-benzimidazol-6-yl)methylene]-1,3-thiazolidine-2,4-dione 495-({1-[2-(4-hydroxyphenyl)ethyl]-1H-benzimidazol-6-yl}methylene)-1,3-thiazolidine-2,4-dione 50 methyl4-{6-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1H-benzimidazol-1-yl}cyclohexanecarboxylate 515-({1-[2-(5-methoxy-1H-indol-3-yl)ethyl]-1H-benzimidazol-6-yl}methylene)-1,3-thiazolidine-2,4-dione 525-({1-[(1-methyl-1H-pyrazol-4-yl)methyl]-1H-benzimidazol-6-yl}methylene)-1,3-thiazolidine-2,4-dione 535-({1-[2-(3,4-dimethoxyphenyl)ethyl]-1H-benzimidazol-6-yl}methylene)-1,3-thiazolidine-2,4-dione 545-({1-[2-(4-phenoxyphenyl)ethyl]-1H-benzimidazol-6-yl}methylene)-1,3-thiazolidine-2,4-dione 555-({1-[4-(trifluoromethyl)benzyl]-1H-benzimidazol-6-yl}methylene)-1,3-thiazolidine-2,4-dione 564-{6-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1H-benzimidazol-1-yl}cyclohexanecarboxylic acid 575-[(1-isobutyl-1H-benzimidazol-6-yl)methylene]-1,3-thiazolidine-2,4-dione585-({1-[2-(1,3-benzodioxol-4-yl)ethyl]-1H-benzimidazol-6-yl}methylene)-1,3-thiazolidine-2,4-dione 595-({1-[2-(2-phenoxyphenyl)ethyl]-1H-benzimidazol-6-yl}methylene)-1,3-thiazolidine-2,4-dione 605-{[1-(3,3-diphenylpropyl)-1H-benzimidazol-6-yl]methylene}-1,3-thiazolidine-2,4-dione 615-{[1-(2-methoxybenzyl)-1H-benzimidazol-6-yl]methylene}-1,3-thiazolidine-2,4-dione 625-{[1-(3-furylmethyl)-1H-benzimidazol-6-yl]methylene}-1,3-thiazolidine-2,4-dione 635-[(1-propyl-1H-benzimidazol-6-yl)methylene]-1,3-thiazolidine-2,4-dione64 5-Quinoxalin-6-ylmethylene-thiazolidine-2,4-dione 655-Quinoxalin-6-ylmethylene-2-thioxo-thiazolidin-4-one 662-Imino-5-quinoxalin-6-ylmethylene-thiazolidin-4-one 675-Benzothiazol-6-ylmethylene-thiazolidine-2,4-dione 685-(3-Methyl-benzofuran-5-ylmethylene)-thiazolidine-2,4-dione 695-(2-Bromo-3-methyl-benzofuran-5-ylmethylene)-thiazolidine-2,4-dione 705-(3-bromo-benzofuran-5-ylmethylene)-thiazolidine-2,4-dione 713-[5-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-benzofuran-3-yl]-acrylicacid ethyl ester 723-[5-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-benzofuran-3-yl]-acrylicacid 735-[3-(3-Oxo-3-piperidin-1-yl-propenyl)-benzofuran-5-ylmethylene]-thiazoli-dine-2,4-dione 74 Methyl1-((3-{5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1-benzofuran-3-yl}prop-2-enoyl)prolinate 75 Methyl1-((3-{5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1-benzofuran-3-yl}prop-2-enoyl)-D-prolinate 76(5-({3-[(3-oxo-3-pyrrolidin-1-ylprop-1-en-1-yl]-1-benzofuran-5-yl}methylene)-1,3-thiazolidine-2,4-dione 775-({3-[3-morpholin-4-yl-3-oxoprop-1-en-1-yl]-1-benzofuran-5-yl}methylene)-1,3-thiazolidine-2,4-dione 78 Methyl1-(3-{5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1-benzofuran-3-yl}prop-2-enoyl)-L-prolinate 79N-cyclohexyl-3-{5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1-benzofuran-3-yl}-N-methylacrylamide 803-{5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1-benzofuran-3-yl}-N-ethyl-N-(2-hydroxyethyl)acrylamide 81N-cyclobutyl-3-{5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1-benzofuran-3-yl}acrylamide 825-({3-[3-azetidin-1-yl-3-oxoprop-1-en-1-yl]-1-benzofuran-5-yl}methylene)-1,3-thiazolidine-2,4-dione 835-({3-[3-(1,3-dihydro-2H-isoindol-2-yl)-3-oxoprop-1-en-1-yl]-1-benzofuran-5-yl}methylene)-1,3-thiazolidine-2,4-dione 845-({3-[3-azepan-1-yl-3-oxoprop-1-en-1-yl]-1-benzofuran-5-yl}methylene)-1,3-thiazolidine-2,4-dione 853-{5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1-benzofuran-3-yl}-N-piperidin-1-ylacrylamide 863-{5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1-benzofuran-3-yl}-N-(pyridin-3-ylmethyl)acrylamide 87N-cyclohexyl-3-{5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1-benzofuran-3-yl}acrylamide 885-({3-[3-(4-methylpiperazin-1-yl)-3-oxoprop-1-en-1-yl]-1-benzofuran-5-yl}methylene)-1,3-thiazolidine-2,4-dione 89N-cycloheptyl-3-{5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1-benzofuran-3-yl}acrylamide 905-({3-[3-(2,5-dihydro-1H-pyrrol-1-yl)-3-oxoprop-1-en-1-yl]-1-benzofuran-5-yl}methylene)-1,3-thiazolidine-2,4-dione 91N-cyclopentyl-3-{5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1-benzofuran-3-yl}acrylamide 923-[5-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-benzofuran-3-yl]-propionicacid ethyl ester 933-[5-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-benzofuran-3-yl]-propionicacid 945-[3-(3-Oxo-3-piperidin-1-yl-propyl)-benzofuran-5-ylmethylene]-thiazol-idine-2,4-dione 956-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester 965-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethylene)-thiazolidine-2,4-dione975-(4-Benzoyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethylene)-thiazolidine-2,4-dione 985-(4-Acetyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethylene)-thiazolidine-2,4-dione 996-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-benzo[1,4]oxazine-4-carboxylicacid tert-butyl ester 100[6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-3-oxo-2,3-dihydro-benzo[1,4]-oxazin-4-yl]-acetic acid methyl ester 101N-Benzyl-2-[6-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl]-acetamide 1025-(4-Butyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethylene)-thiazolidine-2,4-dione 1035-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethylene)-thiazolidine-2,4-dione 1045-(2-Chloro-benzofuran-5-ylmethylene)-thiazolidine-2,4-dione 1055-(3-Amino-benzo[d]isoxazol-5-ylmethylene)-thiazolidine-2,4-dione 1065-(3-Phenylethynyl-benzofuran-5-ylmethylene)-thiazolidine-2,4-dione 1075-Benzo[1,2,5]thiadiazol-5-ylmethylene-thiazolidine-2,4-ione 1085-Benzo[1,2,5]oxadiazol-5-ylmethylene-thiazolidine-2,4-ione 1095-(2-Methyl-benzofuran-6-ylmethylene)-thiazolidine-2,4-dione 1105-(2-Carboxymethyl-benzofuran-6-ylmethylene)-thiazolidine-2,4-dione 1115-(3-Bromo-2-fluoro-2,3-dihydro-benzofuran-6-ylmethylene)-thiazolidine-2,4-dione112 5-(2-Fluoro-benzofuran-6-ylmethylene)-thiazolidine-2,4-dione

The following intermediate aldehydes are commercially available:2,2-Difluoro-1,3-benzodioxole-5-carboxaldehyde,1,3-Benzodioxole-5-carboxaldehyde, 1,4-Benzodioxan-6-carboxaldehyde,9,10-Dioxo-9,10-dihydro-anthracene-2-carbaldehyde,2,3-Dihydro-benzo[b]furan-5-carboxaldehyde,3-Methoxy-4,5-methylenedioxybenzaldehyde.

Thiazolidinedione and Rhodanine are commercially available. Intermediatealdehydes were synthesized according to the protocols as mentionedbelow.

The HPLC, NMR and MS data provided in the examples described below wereobtained as followed: HPLC: column Waters Symmetry C8 50×4.6 mm,Conditions: MeCN/H₂O, 5 to 100% (8 min), max plot 230-400 nm; Massspectra: PE-SCIEX API 150 EX (APCI and ESI), LC/MS spectra: Waters ZMD(ES); ¹H-NMR: Bruker DPX-300 MHz.

The purifications were obtained as followed: Preparative HPLC WatersPrep LC 4000 System equipped with columns Prep Nova-Pak™HR C186 μm 60 Å,40×30 mm (up to 100 mg) or 40×300 mm (up to 1 g). All the purificationswere performed with a gradient of MeCN/H₂O 0.09% TFA.

Intermediate 1: Preparation of 5-formyl-1-benzofuran

Step I Ethyl-2-formyl-4-bromophenoxy acetate

A mixture of 5-bromosalicylaldehyde (50 g, 0.248 mol), ethylbromoacetate(42 g, 0.248 mol) and K₂CO₃ (68 g, 0.49 mol) in dry DM (200 mL) wasstirred at RT for 12 h. The reaction mixture was filtered and filtratediluted with water. The mixture was extracted with diethylether (4×200mL), washed with brine and concentrated to give crudeethyl-2-formyl-4-bromophenoxy acetate (64 g, 90%) as a solid.

Step II: 4-Bromo-2-formylphenoxy acetic acid

A mixture of ethyl-2-formyl-4-bromophenoxy acetate (60 g, 0.209 mol),LiOH (7.5 g, 0.31 mol), THF (250 mL) and water (100 mL) was stirred atRT for 24 h. The reaction mixture was concentrated under reduce pressureand residue acidified with 1.5N HCl to pH=2. The solid precipitateobtained was filtered and dried to give 4-bromo-2-formylphenoxy aceticacid (50 g, 94%).

Step III: 5-Bromo-1-benzofuran

To a mixture of 2-formyl-4-bromophenoxy acetic acid (50 g, 0.192 mol),sodium acetate (100 g, 1.21 mol) in acetic acid (250 mL) at 100° C. wasadded acetic anhydride (100 mL) portions during a period of 3 h. Thereaction mixture was then refluxed for 20 h. The solvent was removed bydistillation and residue diluted with 3N HCl (500 mL) and refluxed for 2h. The reaction mixture was then concentrated under vacuum and productextracted with pet. ether (3×200 mL). The organic layer was washed with10% NaHCO₃ solution and evaporated to give 5-bromo-1-benzofuran (15 g,40%) as a pale yellow liquid.

Step IV: 5-Formyl-1-benzofuran (P1a in scheme 2 for example 9)

A mixture of 5-bromo-1-benzofuran (0.5 g), Mg (0.92 g, 0.038 mol), I₂ (1crystal) in dry THF (2.5 mL) under N₂ atmosphere was refluxed for 30min. To this was added a solution of 5-bromo-1-benzofuran (4.5 g) in 25mL of dry THF) as soon as the 12 color disappear and refluxed foranother 2 h. The reaction mixture was then cooled to −40° C. and addeddry DMF (3.6 g) drop-wise and slowly warmed to RT for a period of 12 h.The reaction mixture was then cooled to 0° C. and acidified with 3N HClto pH=2 and stirred for 30 min. The reaction mixture was then dilutedwith water (500 mL), extracted with ethylacetate (2×200 mL), washed withbrine and dried. The solvent was removed under vacuum and purified bycolumn chromatography over silica gel (pet. ether/CH₂Cl₂) to give5-formyl-1-benzofuran (2 g, 54%) as a liquid. LC-MS: M/Z ESI: 1.47 min,147.34 (M+1).

Intermediate 2: Preparation of4-Methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbaldehyde

Step I: 2-(N-methylamino)-phenol

1 g of benzoxazole was dissolved in 20 ml of THF. 0.9 g of NaBH₄ wereadded under nitrogen and stirring. The suspension was cooled to 0° C.and 0.86 ml of acetic acid dissolved in 5 ml THF were slowly added,keeping the reaction temperature below 5° C. The reaction was stirred at0° C. for 30 minutes and for further 12 hours at room temperature. Thereaction mixture was again cooled to 0° C. and 50 ml of sat. NH₄Clsolution were added carefully. The phases were separated and the aqueouslayer extracted twice with EtOAc. The combined organic layers werewashed with brine, dried over MgSO₄ and filtered. Removal of the solventafforded 0.97 g (of pure 2-(N-methylamino)-phenol.

Step II: 4-Methyl-4H-benzo[1,4]oxazin-3-one

1 g of 2-(N-methylamino)-phenol were dissolved in chloroform, followedby the addition of 10 ml of sat. NaHCO₃ in water. To this suspension wasadded slowly under vigorous stirring a solution of 1 g of2-chloroacetylchloride in acetone. The reaction mixture was stirred for2 hours at room temperature. The layers were separated. The organiclayer was washed with water and dried over Na₂SO₄. After evaporating thesolvent, the red oil was taken up in 30 ml DMF and 1 g of K₂CO₃ wereadded and the slurry was heated at 70° C. for additional 2 hours. Thecyclization was followed by TLC. 200 ml of EtOAc were added and theorganic layer was washed 3× with 0.1N HCl and 5× with brine. Theremaining organic layer was dried over MgSO4 and filtrated. EtOAc wasremoved under reduced pressure affording 1.45 g of pure4-methyl-4H-benzo[1,4]oxazin-3-one.

Step III: 4-Methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6

1 g of AlCl₃ were suspended in 10 ml DCM, 0.5 ml of nitromethane wereadded to dissolve AlCl₃, and the solution was cooled to 0° C.4-Methyl-4H-benzo[1,4]oxazin-3-one (0.5 g, 3.06 mmol) dissolved in DCMwas added to the above solution and stirred for 15 minutes at 0° C. Tothis solution was further added 0.36 ml of bis-chloromethyl-methyletherin DCM. The reaction was stirred at 0° C. for 15 minutes and at roomtemperature for 3 h. The crude reaction mixture was then poured ontoice, the layers were separated and the organic phase was washed withNaHCO₃ and brine. After drying over MgSO₄ and filtration the solvent wasevaporated, which afforded 0.43 g of crude product. The dark oil waspurified by flash chromatography using EtOAc and cyclohexane as eluents,affording 0.2 g (37%) of4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbaldehyde ascolourless solid.

HPLC: 2.07 min. LC-MS: M/Z ESI: 1.31 min, 192.28 (M+1).

Intermediate 3: Preparation of4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-carbaldehyde

Step I: 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine

0.97 g of 2-(N-methylamino)-phenol were dissolved in 50 ml acetone,followed by the addition of 2 g of K₂CO₃ dissolved in water. To thissuspension was added slowly a solution of 2.66 g of dibromoethane inacetone. The reaction mixture was stirred for 22 hours under reflux.Acetone was evaporated and 200 ml of EtOAc were added and the organiclayer was washed 3× with 0.1N HCl and 3× with brine. The remainingorganic layer was dried over MgSO4 and filtrated. EtOAc was removedunder reduced pressure affording 1 g of pure4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine.

Step II: 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-carbaldehyde

4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine dissolved in 200 ul DMF underArgon. POCl₃ was added under Argon. The reaction was heated and a closedvial at 90° C. for 75 min. 1 ml of NaAc in water was added and stirredwhile a brown oil was formed. The oil was extracted with DCM. Theorganic layer was washed with brine, dried and evaporated to dryness,affording 0.18 g (76%) of4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-carbaldehyde as colourlesssolid.

LC-MS: M/Z ESI: 1.37 min, 178.35 (M+1).

Intermediate 4: Preparation of 1,3-Dihydroisobenzofuran-5-carbaldehyde

Step I (1,3-Dihydro-isobenzofuran-5-yl)-methanol

In a round bottom flask with reflux condenser were placed 1.0 g of3-Prop-2-ynyloxy-propyne and 2.08 g of propargylic alcohol in 10 mlethanol, followed by the addition of 9.8 mg oftris(triphenylphosphine)rhodium chloride (Wilkinson catalyst) at roomtemperature. The reaction was heated up to 70° C., while the reactioncolour turned yellow rapidly. After 1 day stirring at r.t., TLC analysisshowed complete conversion of the starting material. The solvent wasevaporated, diluted with DCM and extracted with H₂O, dried over MgSO4.The brown mixture was purified by flash chromatography using 8/2cyclohexane/AcOEt as mobile phase affording(1,3-Dihydro-isobenzofuran-5-yl)-methanol as a colourless pure solid(0.92 g, 60%).

Step II: 1,3-Dihydroisobenzofuran-5-carbaldehyde

(1,3-Dihydro-isobenzofuran-5-yl)-methanol (440 mg, 2.9 mmol) wasdissolved in 20 ml of DCM.1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martinreagent) (1.3 g, 3.2 mmol) was added and the reaction was stirred atr.t. for 4 h. The reaction mixture was diluted with ether and extracted2× with NaOH 1N, 2× with H₂O and dried over MgSO₄. The crude product wassufficiently pure and used without any further purification.

HPLC: 2.00 min. LC-MS: M/Z ESI: 1.50 min, 149.18 (M+1).

Intermediate 5: Preparation of Quinoline-6-carbaldehyde

Step I: Quinolin-6-yl-methanol

5 g of methyl quinoline-6-carboxylate was dissolved in dry THF. UnderArgon was added LiAlH₄ 1M in THF (2 eq.) at −20° C. The solution wasstirred at that temperature for 1 h. Isopropanol was slowly added andthe crude filtered through celite and washed with DCM. Concentrationgave 3.6 g (85%) of pure alcohol.

HPLC: 1.10 min. LC-MS: M/Z ESI: 0.91 min, 160.43 (M+1).

Step II: Quinoline-6-carbaldehyde

2 g of quinolin-6-yl-methanol was dissolved in DCM. 15 g of MnO2 wasadded and the reaction mixture was stirred for 5 h. The crude filteredthrough celite and washed extensively with DCM. Concentration gave 1.85g (93%) of pure aldehyde.

HPLC: 0.8 min. LC-MS: M/Z ESI: 1.07 min, 158.37 (M+1). ¹H NMR (DMSO-d6)δ 10.19 (s, 1H), 9.06 (t, J=3 Hz, 1H), 8.6-8.66 (m, 2H), 8.15 (s, 2H),7.68 (dd, J=3 Hz, 9 Hz, 1H).

The following intermediate was synthesized accordingly using thesuitable starting materials:

Intermediate 6: Preparation of 3-Methyl-benzo[d]isoxazole-5-carbaldehyde

HPLC: 2.06 min. LC-MS: M/Z ESI: 1.26 min, 162.31 (M+1). ¹H NMR (DMSO-d6)δ 10.10 (s, 1H), 8.52 (s, 1H), 8.16 (d, J=12 Hz, 1H), 8.15 (s, 2H), 7.90(d, J=9 Hz, 1H), 2.63 (s, 3H).

Intermediate 7: Preparation of 4-Chloro-quinazoline-6-carboxylic acidmethyl ester

Step I: 4-Nitro isophthalic acid

A mixture of 3-methyl-4-nitrobenzoic acid (150 g, 0.825 mol), pyridine(1.5 L) and water (1.5 L) was heated to reflux. To the hot reactionmixture was added KMnO₄ (10 mol) portion wise and reflux for 72 h. Thehot reaction mixture was filtered through celite and washed with hotwater. The filtrate was concentrated under vacuum, residue diluted withwater (750 mL) and acidified with con. HCl at 0° C. The solid obtainedwas filtered, washed with water and dried under vacuum to give 4-nitroisophthalic acid (98 g, 56%).

TLC, Chloroform/Methanol, 7:3, R_(f)=0.2

Step II: 4-Amino isophthalic acid

To a solution of 4-nitro isophthalic acid (98 g, 0.457 mol) in methanol(5 L) was added Pd/C (20%) and hydrogenated at RT for 4 h. The reactionmixture was filtered through celite and filtrate concentrated undervacuum to give 4-amino isophthalic acid (72 g, 87%) as a solid.

TLC, Chloroform/Methanol, 7:3, R_(f)=0.4

Step III: 4-Oxo-3,4-dihydroquinazoline-6-carboxylic acid

A mixture of 4-amino isophthalic acid (17 g, 0.093 mol) and formamide(85 mL) was heated at 180° C. for 5 h. The reaction mixture was cooledto RT and added acetone. The solid precipitate thus obtained was stirredfor 2 h, filtered and dried to give4-oxo-3,4-dihydroquinazoline-6-carboxylic acid (11 g, 61%).

TLC, Chloroform/Methanol, 8:2, R_(f)=0.25

Step IV: 4-Oxo-3,4-dihydroquinazoline-6-methyl carboxylate

To a solution of 4-oxo-3,4-dihydroquinazoline-6-carboxylic acid (24 g,0.126 mol) in dry methanol (800 mL) was added thionylchloride (37 g) at5° C. and then refluxed at 80° C. for 5 h. The reaction mixture wasconcentrated under vacuum and crude taken in ethylacetate (250 mL). Theorganic layer was washed with 10% aqueous NaHCO₃, water, brine anddried. The solvent was removed under vacuum to give4-oxo-3,4-dihydroquinazoline-6-methyl carboxylate (24 g, 92%) as asolid.

TLC, Chloroform/Methanol, 8:2, R=0.6

Step V: Methyl-4-chloroquinazoline-6-carboxylate

A mixture of 4-oxo-3,4-dihydroquinolin-6-methyl carboxylate (12 g, 0.058mol) and phosphorylchloride (180 mL) was heated to reflux for 7 h.Excess phosphorylchloride was distilled off and crude taken inethylacetate (250 mL). The organic layer was washed with 10% aqueousNaHCO₃ solution, water, brine and dried. The solvent was removed undervacuum and crude purified by column chromatography over silica gel (30%ethylacetate in pet. ether) to givemethyl-4-chloroquinazoline-6-carboxylate (4.5 g, 34%) as a solid.

TLC, pet. ether/EtOAc, 1:1, R_(f)=0.65

LC-MS: M/Z ESI: 1.50 min, 223.19 (M+1). ¹H NMR (DMSO-d6) δ 8.66 (d,J=1.9 Hz, 1H), 8.39 (s, 1H), 8.30 (dd, J=0.6 Hz, 8.5 Hz, 1H), 7.79 (d,J=8.5 Hz, 1H), 3.90 (s, 3H).

Intermediate 8: Preparation of 4-Methoxy-quinazoline-6-carboxylic acidmethyl ester

200 mg of methyl-4-chloroquinoline-6-carboxylate were stirred in 5 mlMeOH in the presence of 1 eq. of DIEA at 60° C. for 24 h. MeOH wasevaporated and the crude residue was taken up in EtOAc and washed withNH₄Cl affording a white solid sufficiently pure for the next step.

HPLC: 2.3 min. LC-MS: M/Z ESI: 1.19 min, 219.17 (M+1).

The following intermediate was synthesized according to the synthesis ofintermediate 8:

Intermediate 9: Preparation of 4-Methylamino-quinazoline-6-carboxylicacid methyl ester

HPLC: 1.12 min. LC-MS: M/Z ESI: 1.06 min, 218.31 (M+1).

Intermediate 10: Preparation of 4-Methoxy-quinazoline-6-carbaldehyde

This intermediate was prepared according to the synthesis ofintermediate 5 starting from 4-Methoxy-quinazoline-6-carboxylic acidmethyl ester.

HPLC: 1.41 min. LC-MS: M/Z ESI: 1.24 min, 189.31 (M+1).

Intermediate 11: Preparation of 4-Methylamino-quinazoline-6-carbaldehyde

This intermediate was prepared according to the synthesis ofintermediate 5 starting from 4-Methylamino-quinazoline-6-carboxylic acidmethyl ester.

HPLC: 1.3 min. LC-MS: M/Z ESI: 0.90 min, 188.34 (M+1).

Intermediate 12: Preparation of 4-Chloro-quinazoline-6-carbaldehyde

Step I: 4-Chloroquinazoline-6-yl methanol

To a solution of methyl-4-chloroquinazoline-6-carboxylate (3.5 g, 0015mol) in dry THF (35 mL) at −25° C. was added DIBAL-H (4.4 g, 0.031 mol)and stirred at −25° C. to RT for 2 h. The reaction mixture was cooled to−10° C. and quenched with 10% aqueous NaHCO₃ (9 mL). The reactionmixture was extracted with ethylacetate (100 mL), washed with water,brine and dried. The solvent was removed under vacuum to give4-chloroquinoline-6-yl methanol (2 g, 66%).

TLC, Chloroform/Methanol, 8:2, R_(f)=0.35

Step II: 4-Chloroquinazoline-6-carboxaldehyde

To a solution of 4-chloroquinazoline-6-yl-methanol (3.5 g, 0.018 mol) indry CH₂Cl₂ (100 mL) was added Dess-Martin periodinane (8.4 g, 0.019 mol)and stirred at RT for 30 min. The reaction mixture was washed with 10%aqueous NaHCO₃ (75 mL), water, brine and dried. The solvent was removedunder vacuum to give 4-chloroquinazoline-6-carboxaldehyde (3 g, 88%) aspale yellow solid.

TLC, Chloroform/Methanol, 9:1, R_(f)=0.6

Intermediate 13: Preparation of 4-Phenyl-quinazoline-6-carbaldehyde

4-Chloro-quinazoline-6-carbaldehyde (50 mg, 0.26 mmol), Pd(PPh₃)₄ (13mg, 0.01 mmol), phenylboronic acid (63 mg, 0.52 mmol) and sodiumcarbonate (sat. sol: 50 ul) were heated up in toluene at 100° C. for 12h. After evaporation of the solvents, the residue was taken up in ethylacetate and washed with brine twice. Organic phases were thenconcentrated and raw materiel was purified on silica gel using DCM/EtOH95:5 as eluents to give 50 mgs (82%) of the desired cpd with a 85%purity.

HPLC: 2.68 min. LC-MS: M/Z ESI: 1.25 min, 235.30 (M+1).

Intermediate 14: Preparation of4-Dimethylamino-quinazoline-6-carbaldehyde

4-Chloro-quinazoline-6-carbaldehyde (200 mg, 1 mmol) was dissolved in 10ml dioxane. To this solution was added a solution of dimethylamine inwater (Seq.). The mixture was stirred during 2 h at r.t. Evaporation ofthe solvents and remaining amine under high vacuum afforded pure4-Dimethylamino-quinazoline-6-carbaldehyde as a yellow solid, which wasused for the next step without further purification (190 mg=91%).

HPLC: 0.91 min. LC-MS: M/Z ESI: 1.23 min, 202.33 (M+1). ¹H NMR (CDCl₃):δ 10.19 (s, 1H), 8.70 (s, 1H), 8.50 (d, J=3 Hz, 1H), 8.15 (dd, J=3 Hz, 9Hz, 1H), 7.88 (d, J=9 Hz, 1H).

The following intermediates were synthesized in a similar way using thesuitable amines as nucleophiles.

M/Z N^(o). Intermediate ESI:(M + 1). 154-Piperidin-1-yl-quinazoline-6-carbaldehyde 242.27 164-Amino-quinazoline-6-carbaldehyde 174.18 174-Benzylamino-quinazoline-6-carbaldehyde 264.30 184-[(Pyridin-2-ylmethyl)-amino]-quinazoline-6-carbaldehyde 265.33 194-[(Pyridin-3-ylmethyl)-amino]-quinazoline-6-carbaldehyde 265.33 204-(4-Methyl-piperazin-1-yl)-quinazoline-6-carbaldehyde 257.31 214-Diethylamino-quinazoline-6-carbaldehyde 230.28 224-Morpholin-4-yl-quinazoline-6-carbaldehyde 244.26 231-(6-Formyl-quinazolin-4-yl)-piperidine-3-carboxylic acid ethyl ester314.36 24 1-(6-Formyl-quinazolin-4-yl)-pyrrolidine-2-carboxylic acidtert- 328.39 butylester 251-(6-Formyl-quinazolin-4-yl)-piperidine-4-carboxylic acid ethyl ester314.36 26 4-(4-Hydroxy-piperidin-1-yl)-quinazoline-6-carbaldehyde 258.3027 4-(4-Methyl-piperidin-1-yl)-quinazoline-6-carbaldehyde 256.32 284-(4-Phenethyl-piperidin-1-yl)-quinazoline-6-carbaldehyde 346.42 294-(4-Benzyl-piperidin-1-yl)-quinazoline-6-carbaldehyde 332.40 304-[4-(4-Fluoro-phenyl)-piperidin-1-yl]-quinazoline-6-carbaldehyde 336.3831 4-(4-Pyrimidin-2-yl-piperazin-1-yl)-quinazoline-6-carbaldehyde 321.36

Intermediates 32: Preparation of Methyl-benzotriazole-5-carboxylic acidmethyl ester

1 g of Benzotriazole-5-carboxylic acid methyl ester (5.64 mmol) wasdissolved in 20 ml DMF at 0° C. To this solution was added 1 eq. of NaH(60%) at 0° C. The mixture was stirred for 30 min at 0° C., 801 mg (1eq.) of Methyliodide were slowly added, and the resulting reactionmixture was stirred for 2 h at rt. EtOAc was added and the organic layerwas washed extensively with brine and water, dried over MgSO4 andfiltered to afford 1 g of crude Methyl-benzotriazole-5-carboxylic acidmethyl ester as three different regioisomers. The separation wasperformed on silica gel using EtOAc/CH 3:7 as eluents.

Intermediate 32a: 2-Methyl-2H-benzotriazole-5-carboxylic acid methylester

2-Methyl-2H-benzotriazole-5-carboxylic acid methyl ester eluted as firstfraction (250 mg, 22%). HPLC: 2.32 min. ¹H NMR (DMSO-d6) δ 8.56 (s, 1H),8.02 (d, J=9 Hz, 1H), 7.93 (d, J=9 Hz, 1H), 4.55 (s, 3H), 3.90 (s, 1H).

Intermediate 32b: 3-Methyl-3H-benzotriazole-5-carboxylic acid methylester

3-Methyl-3H-benzotriazole-5-carboxylic acid methyl ester eluted as2^(nd) fraction (130 mg, 12%). HPLC: 2.03 min. ¹H NMR (DMSO-d6) δ 8.56(s, 1H), 8.13 (d, J=6 Hz, 1H), 7.93 (d, J=9 Hz, 1H), 4.39 (s, 3H), 3.92(s, 3H).

Intermediate 32c: 1-Methyl-1H-benzotriazole-5-carboxylic acid methylester

1-Methyl-1H-benzotriazole-5-carboxylic acid methyl ester eluted as3^(rd) fraction (135 mg, 12%). HPLC: 2.03 min. ¹H NMR (DMSO-d6) δ 8.62(s, 1H), 8.11 (d, J=9 Hz, 1H), 7.97 (d, 9 Hz, 1H), 4.35 (s, 3H), 3.90(s, 3H).

Intermediate 33: 2-Methyl-2H-benzotriazole-5-carbaldehyde

This intermediate has been synthesized according to the synthesis ofintermediate 5 using 2-Methyl-2H-benzotriazole-5-carboxylic acid methyl(intermediate 32a) ester as starting point.

HPLC: 1.88 min. ¹H NMR (DMSO-d6) δ 10.12 (s, 1H), 8.65 (s, 1H), 8.06 (d,J=9 Hz, 1H), 7.85 (d, J=9 Hz, 1H), 4.57 (s, 3H).

Intermediate 34: 3-Methyl-3H-benzotriazole-5-carbaldehyde

This intermediate has been synthesized according to the synthesis ofintermediate 5 using 3-Methyl-3H-benzotriazole-5-carboxylic acid methylester (intermediate 32b) as starting point.

HPLC: 1.49 min. ¹H NMR (DMSO-d6) δ 10.18 (s, 1H), 8.54 (s, 1H), 8.20 (d,J=9 Hz, 1H), 7.88 (d, J=9 Hz, 1H), 4.41 (s, 3H).

Intermediate 35: 1-Methyl-1H-benzotriazole-5-carbaldehyde

This intermediate has been synthesized according to the synthesis ofintermediate 5 using 1-Methyl-1H-benzotriazole-5-carboxylic acid methylester as starting point (intermediate 32c).

HPLC: 1.49 min. LC-MS: M/Z ESI: 1.07 min, 162.32 (M+1). ¹H NMR (DMSO-d6)δ 10.13 (s, 1H), 8.70 (s, 1H), 8.05 (s, 2H), 4.36 (s, 3H).

Intermediate 36:5-(4-Amino-3-ethylamino-benzylidene)-thiazolidine-2,4-dione

Step I: 3-Fluoro 4-nitro benzyl alcohol (Bioorg. Med. Chem. 7, 1999,2647)

To an ice-cooled suspension of NaBH₄ (204 mg, 5.4 mmol, 2 eq.) in THF(10 mL) was added dropwise 3-fluoro 4-nitro benzoic acid (500 mg, 2.7mmol, 1 eq.) in THF (10 mL) over 30 minutes. BF₃-Et₂O (7.3 mmol, 2.7eq.) was then added dropwise over 30 minutes. The solution was stirredat room temperature over night. 1N HCl was added dropwise to quenchNaBH₄ excess. The solvent was removed in vacuo, the residue dissolved inDCM, washed with water, brine. The organic layer was then dried overMgSO₄ and the solvent removed in vacuo to give 425 mg of 3-fluoro4-nitro benzyl alcohol (92% yield). The compound was used in thefollowing step with no further purification.

¹H NMR: δ=(400 MHz, CDCl₃): 7.97 (m, 1H), 7.28 (m, 1H), 7.18 (m, 1H),4.75 (m, 2H).

Step II: 3-Fluoro 4-nitro benzyl aldehyde

3-fluoro 4-nitro benzyl alcohol (116 mg, 0.68 mmol, 1 eq.) was dissolvedin DCM (10 ml) and treated with MnO₂ (580 mg, 6.73 mmol, 10 eq.) and thesuspension stirred at room temperature over night. MnO₂ was filtered offthe suspension using celite and the solvent evaporated to give thecorresponding aldehyde as a white solid (66% yield).

¹H NMR: δ=(400 MHz, CDCl₃): 9.98 (s, 1H, CHO), 8.08 (m, 1H, ArH), 7.78(m, 2H, ArH).

Step III: 5-(3-Fluoro-4-nitro-benzylidene)-thiazolidine-2,4-dione (J.Med. Chem. 37, 2, 1994, 322)

A mixture of 3-fluoro 4-nitro benzyl aldehyde (280 mg, 1.65 mmol, 1eq.), thiazolidine-dione (193 mg, 1.65 mmol, 1 eq.) and β-alanine (95mg, 1.1 mmol, 0.65 eq.) in acetic acid (5 mL) was stirred over night at100° C. The cooled reaction mixture was added to water and stirred for 1hour. The precipitated product was filtered and washed with water anddried to yield the final product as a yellow/orange solid (77% yield).

¹H NMR: δ=(400 MHz, (CD₃)₂CO): 8.0 (m, 1H, ArH), 7.68 (m, 2H, ArH), 7.53(s, 1H, CH═C).

Step IV: 5-(3-Ethylamino-4-nitro-benzylidene)-thiazolidine-2,4-dione

5-(3-Fluoro-4-nitro-benzylidene)-thiazolidine-2,4-dione (200 mg, 0.75mmol, 1 eq.), was dissolved in DME (6 mL) and TEA (208 μL, 1.5 mmol, 2eq.) and a solution of ethylamine (2 eq.) was added. The reactionmixture was shaken at 60° C. over night. The solvent was removed invacuo and residue dissolved in ethyl acetate and washed with 10%ammonium chloride aqueous solution. The organic layer was dried onNa₂SO₄ and the solvent evaporated to give the corresponding anilinederivative as either red oil, which was used for the next step withoutfurther purification.

Step V: 5-(3-Ethylamino-4-amino-benzylidene)-thiazolidine-2,4-dione

To a stirred solution of5-(3-Ethylamino-4-nitro-benzylidene)-thiazolidine-2,4-dione in THF, asolution of sodium hydrosulfite (3 eq.) in water was slowly addedfollowed by an aqueous solution of K₂CO₃. The reaction mixture wasrefluxed over night. THF was removed in vacuo and residue extracted withethyl acetate The organic layer was dried on Na₂SO₄ and the solventevaporated to give the corresponding aniline derivative, which was usedwithout any further purification.

The following intermediates were synthesized in a similar way using thesuitable amines as nucleophiles as described in step IV of intermediate36. The so-obtained3-alkylamino-4-nitro-benzylidene)-thiazolidine-2,4-diones were reducedas described in step V of intermediate 36 affording3-alkylamino-4-amino-benzylidene)-thiazolidine-2,4-diones.

M/Z N^(o). Intermediate ESI:(M + 1) 375-[4-Amino-3-(4-phenyl-butylamino)-benzylidene]-thiazolidine-2,4-dione368.2 385-{4-Amino-3-[2-(4-trifluoromethyl-phenyl)-ethylamino]-benzylidene}-408.12 thiazolidine-2,4-dione 395-{4-Amino-3-[2-(4-hydroxy-phenyl)-ethylamino]-benzylidene}- 356.13thiazolidine-2,4-dione 404-[2-Amino-5-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-phenylamino]-376.35 cyclohexanecarboxylic acid methyl ester 415-{4-Amino-3-[2-(1H-indol-3-yl)-ethylamino]-benzylidene}-thiazolidine-409.21 2,4-dione 425-{4-Amino-3-[(1-methyl-1H-pyrazol-4-ylmethyl)-amino]-benzylidene}-331.1 thiazolidine-2,4-dione 435-{4-Amino-3-[2-(3,4-dimethoxy-phenyl)-ethylamino]-benzylidene}- 400.21thiazolidine-2,4-dione 445-[4-Amino-3-(4-trifluoromethyl-benzylamino)-benzylidene]- 394.15thiazolidine-2,4-dione 454-[2-Amino-5-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-phenylamino]-362.17 cyclohexanecarboxylic acid 465-(4-Amino-3-isobutylamino-benzylidene)-thiazolidine-2,4-dione 292.22 475-[4-Amino-3-(2-benzo[1,3]dioxol-4-yl-ethylamino)-benzylidene]- 384.26thiazolidine-2,4-dione 485-{4-Amino-3-[2-(2-phenoxy-phenyl)-ethylamino]-benzylidene}- 432.28thiazolidine-2,4-dione 495-[4-Amino-3-(3,3-diphenyl-propylamino)-benzylidene]-thiazolidine-2,4-430.27 dione 505-(4-Amino-3-prop-2-ynylamino-benzylidene)-thiazolidine-2,4-dione 274.2151 5-[4-Amino-3-(2-methoxy-benzylamino)-benzylidene]-thiazolidine-2,4-356.23 dione 525-{4-Amino-3-[(furan-3-ylmethyl)-amino]-benzylidene}-thiazolidine-2,4-316.21 dione 535-(4-Amino-3-propylamino-benzylidene)-thiazolidine-2,4-dione 278.16 545-{4-Amino-3-[2-(4-phenoxy-phenyl)-ethylamino]-benzylidene}- 432.23thiazolidine-2,4-dione

Intermediate 55: Quinoxaline-6-carbaldehyde

Step I: Quinoxaline-6-carbonyl chloride

In a 1 l 3 neck flask was placed Quinoxaline-6-carboxylic acid (20.2 g)in 500 ml of THF. To this solution was slowly added thionylchloride (42ml, Seq.). The reaction mechanically stirred was warmed up to reflux andfollowed by HPLC quenching the sample with NH₄OH. After 3 h at reflux nomore starting material was present, the solvent was removed underreduced pressure and SOCl₂ was chased with toluene 3 times. The solidwas suspended in 100 ml EtOAc and filtered to obtain 23.47 g of a beigesolid.

HPLC: 1.114 min. ¹H NMR (DMSO-d6) δ 9.01-7.40 (m, 5H).

Step I: Quinoxaline-6-carbaldehyde

In a 1 l 3-neck flask under argon was placed Quinoxaline-6-carbonylchloride in 600 ml of DME. To this solution was added lithiumtri-tert-butoxyaluminohydride (1 eq.) at −78° C. over 1.5 h. Thereaction was kept at that temperature for 5 h. Then ice was added, andthe reaction was diluted with AcOEt and filtrated over celite. The twolayers were separated and the organic phase was washed with NaHCO₃ sat.Quinoxaline-6-carbaldehyde was obtained upon evaporating the solvent in73% yield as yellowish solid.

HPLC: 1.49 min. LC-MS: M/Z ESI: 0.81 min, 159.37 (M+1). ¹H NMR (CDCl3) δ10.28 (s, 1H), 8.97 (s, 2H), 8.61 (s, 1H), 8.27 (q, 6 Hz, 9 Hz, 2H).

Intermediate 56: Benzothiazole-6-carbaldehyde

This intermediate was synthesized as seen in the synthesis ofintermediate 55 starting from Benzothiazole-6-carboxylic acid. Theoverall yield was 38%.

HPLC: 1.92 min. LC-MS: M/Z ESI: 0.97 min, 164.27 (M+1). ¹H NMR (DMSO-d6)δ 10.1 (s, 1H), 9.60 (s, 1H), 8.60 (s, 1H), 8.20 (m, 1H), 8.10 (d, 1H).

Intermediate 57: 3-Methyl-benzofuran-5-carbaldehyde

This intermediate was accessed through the same route as intermediate 1using Ethyl-2-acetyl-4-bromophenoxy acetate as starting material.Overall yield 50%.

LC-MS: M/Z ESI: 1.55 min, 161.34 (M+1). ¹H NMR (DMSO-d6) δ 10.1 (s, 1H),8.21 (d, J=1.5 Hz 1H), 7.92 (d, J=1.3 Hz, 1H), 7.88-7.84 (dd, J=1.6 Hz,1H), 7.73-7.71 (d, J=8.5 Hz, 1H), 2.25 (s, 3H).

Intermediate 58: 3-Bromo-benzofuran-5-carbaldehyde

Step I: 2,3-Dibromo-2,3-dihydro-benzofuran-5-carbaldehyde

Intermediate 1 (2 g, 13.7 mmol) was dissolved in 10 ml CHCl3 and cooledto −10° C. To this was added a solution of Br₂ in CHCl₃ (1.55 eq.,c=4.162 mol/l). The reaction mixture turned dark and was allowed toreach r.t. during 1 h. HPLC indicated complete addition of bromine. Thesolvent and remaining bromine were evaporated under reduced pressureaffording a reddish oil (4.1 g=90%), which was used for the next stepwithout further purification.

HPLC: 3.43 min

Step II: 3-Bromo-1-benzofuran-5-carbaldehyde

To a solution of 2,3-dibromo-2,3-dihydro-1-benzofuran-5-carbaldehyde(4.1 g) in dry ethanol (15 mL) was added a solution of KOH (2.2 eq.) indry ethanol (14 mL) and refluxed at 70° C. for 1 h. The reaction mixturewas cooled, diluted with water and extracted with EtOAc (3×50 mL). Theorganic layer was washed with water, brine and dried. The solvent wasremoved under vacuum and the residue was purified by flashchromatography (pet. ether/EtOAc 99.5:0.5) to give the title compound asa pale yellow solid (2.91 g (80% pure), yield=78%).

HPLC: 3.35 min. ¹H NMR (DMSO-d₆, 300 MHz) δ 10.12 (s, 1H), 8.47 (s, 1H),8.14 (d, J=1.5 Hz, 1H), 7.97 (dd, J=8.6, 1.5 Hz, 1H), 7.87 (d, J=8.6 Hz,1H).

Intermediate 59: 3-Phenylethynyl-benzofuran-5-carbaldehyde

In a dry flask 3-Bromo-1-benzofuran-5-carbaldehyde (1 g, 4.4 mmol) weredissolved in anhydrous THF (50 ml). To this was added under Argon Bis(triphenylphosphine) palladium(II) chloride (160 mg, 0.2 mmol), TEA(2.81 mL, 5 eq.), CuI (40 mg, 0.2 mmol) and Phenylacetylene (897 mg, 8.8mmol). The reaction was heated at 55° C. for 2 days. The crude wasfiltered through celite and purified on silicagel using as eluentcyclohexan-ethyl acetate (7-3) affording 680 mg (yield: 56%)

HPLC: 4.71 min. ¹H NMR (DMSO-d6) δ 10.14 (s, 1H), 8.64 (s, 1H), 8.38 (s,1H), 7.97 (dd, J=1.5 Hz, 8.3 Hz, 1H), 7.90 (d, J=8.6 Hz, 1H), 7.65 (m,2H), 7.46 (m, 3H).

Intermediate 60: 3-(5-Formyl-benzofuran-3-yl)-acrylic acid ethyl ester

In a sealed tube 3-Bromo-1-benzofuran-5-carbaldehyde (500 mg, 2.22 mmol)was dissolved in 7 ml of ACN. To this solution was added PPh₃ (1.16 g,4.44 mmol), Pd(II)acetate (500 mg, 2.2 mmol), Et3N (073 mL, 5.55 mmol)and finally acrylic acid ethyl ester (2.41 ml, 22 mmol). The tube wassealed and the reaction was heated at 120° C. for one hour. The crudewas filtered on celite to eliminate inorganic contaminations. Thesolvents were evaporated and the crude was purified by silicagelchromatography using cyclohexane-AcOEt 95-5 to 50-50. A pale yellowsolid was obtained (400 mg, yield:42%).

HPLC: 3.69 min. ¹H NMR (DMSO-d6) δ 10.15 (s, 1H), 8.70 (s, 2H), 7.97 (d,J=9 Hz 1H), 7.88 (s, 1H), 7.82 (s, 1H), 6.76 (d, J=15 Hz, 1H), 4.23 (q,J=6 Hz, 12 Hz, 2H), 1.28 (t, J=9 Hz, 3H).

Intermediate 61: 2,3-Dihydro-benzo[1,4]oxazine-4,6-dicarboxylic acid4-tert-butyl ester 6-methyl ester

Step I: 3-Amino-4-hydroxy-benzoic acid methyl ester

To a 2000 ml three-necked flask containing 3-Nitro-4-hydroxy-benzoicacid methyl ester (43 g, 2188 mmol) in MeOH (860 ml; 20 vols) was addedpalladium on carbon in water (2 g in 10 ml of water). Ammonium formiate(68.76 g, 5 eq.) was added in a single portion under stirring. After 2to 3 minutes a suspension was observed, and temperature raised from 20°C. to 30° C. Ice bath was used to cool reaction mixture to 20° C. andthe reaction was stirred at 20° C. for 40 minutes until completion (nomore yellow color). Reaction mixture was filtered on silica plug, rinsedwith MeOH, and the filtrate was concentrated under vacuum to give agreen oil which was taken up in ethyl acetate (400 ml). The organicphase was washed twice with water, dried over MgSO₄, filtered andconcentrated to give a cream solid m=31.35 g (86%).

LC-MS: M/Z ESI: 0.81 min, 168.37 (M+1)

Step II: 3,4-Dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methylester*hydrochloride

To a 2000 ml three-necked flask under N₂ containing3-Amino-4-hydroxy-benzoic acid methyl ester (31.35 g, 187 mmol) inanhydrous DMF (630 ml; 20 vols) at RT, was added K₂CO₃ (103 g, 4 eq.) inone portion followed by 1,2dibromoethane (65 ml, 4 eq.) in one portion.The reaction mixture was stirred at 70° C. for 12 h. Temperature wasallowed to cool down to RT, and HCl1N was added until pH=8, andextraction was performed using diethyl ether (3*200 ml). The organicphase was washed with water (2*200 ml) and dried over MgSO₄ andconcentrated to afford a brown red oil with solid, which was taken upagain in diethyl ether (450 ml) and THF (50 ml) and filtered to remove awhite solid. To the filtrate was added HCl1N, and diethyl ether (130 ml)was added, suspension was stirred at RT for 5 minutes and filtered togive 27.6 g of crude product. The aqueous phases were again extractedwith ethyl acetate to afford additional 6.23 g of product. The combinedfractions (32 g) were recrystallised from EtOH (420 ml; 13 vols) to giveafter filtration and drying a white powder (19.47 g (16.37 g freebase)), yield=40%.

HPLC: 1.954 min. LC-MS: M/Z ESI: 1.27 min, 194.45 (M+1).

Step III: 2,3-Dihydro-benzo[1,4]oxazine-4,6-dicarboxylic acid4-tert-butyl ester 6-methyl ester

To a 500 ml three-necked flask containing3,4-Dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methylester*hydrochloride in suspension in THF (145 ml; 10 vols) under N₂,DIEA (27 ml, 2.5 eq.) was added in one portion at RT and partialsolubilisation was observed. Boc anhydride/(16.4 g, 1.2 eq.) was addedin one portion and the reaction was stirred at 65° C. for 5 days. Duringthat time several small portions of 0.2 eq. of Boc₂O and DIEA wereadded. THF was removed under vacuum and the residue was taken up in DCM150 ml The organic phase was washed with a saturated solution of NaHCO₃and then with brine. After drying over MgSO₄ and filtration, volatileswere removed under vacuum and the residue was recrystallised from EtOH(80 ml) to give cream crystals (14.8 g, 76%).

HPLC: 4.038 min. ¹H NMR (CDCl3) δ8.49 (s, 1H), 7.68 (dd, J=3 Hz, 9 Hz,1H), 6.89 (d, J=9 Hz, 1H), 4.30 (q, J=3 Hz, 9 Hz, 2H), 3.89 (m, 5H),1.62 (s, 9H).

Intermediate 62: 6-Formyl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylicacid tert-butyl ester

This intermediate was accessed through oxido-reduction as described forintermediate 5.

HPLC: 3.727 min. LC-MS: M/Z ESI: 1.81 min, 264.34 (M+1). ¹H NMR(DMSO-d6) δ 9.83 (s, 1H), 8.35 (s, 1H), 7.53 (d, J=6 Hz, 1H), 7.05 (d,J=9 Hz, 1H), 4.31 (t, J=3 Hz, 2H), 3.83 (t, J=6 Hz, 2H), 1.50 (s, 9H).

Intermediate 63: 6-Formyl-benzo[1,4]oxazine-4-carboxylic acid tert-butylester

Step I: 2,3-Dibromo-2,3-dihydro-benzo[1,4]oxazine-4,6-dicarboxylic acid4-tert-butyl ester 6-methyl ester

To a solution of 2,3-Dihydro-benzo[1,4]oxazine-4,6-dicarboxylic acid4-tert-butyl ester 6-methyl ester (500 mg, 1.7 mmol) in dry carbontetrachloride (20 ml) was added N-Bromosuccinimide (667 mg, 3.75 mmol)and a catalytic amount of benzoylperoxide. The resulting mixture wasstirred and heated with a bulp lamp (100 W) at reflux for 45 min. Themixture was allowed to cool and the succinimide was filtered off. Thefiltrate was evaporated to yield an oil (767 mg, 99%) sufficiently pureto be used for the next step.

HPLC: 3.978 min

Step II: Benzo[1,4]oxazine-4,6-dicarboxylicacid 4-tert-butyl ester6-methyl ester

2,3-Dibromo-2,3-dihydro-benzo[1,4]oxazine-4,6-dicarboxylic acid4-tert-butyl ester 6-methyl ester (767 mg, 1.7 mmol) from proceedingstep was stirred in acetone (14 ml) at RT for 2 h with NaI (1.27 g, 8.5mmol). The solvent was removed, EtOAc, water and 1 M sodium thiosulfatewere added. After separating phases the organic layer was washed withbrine. The solvent was concentrated and the crude was purified on silicagel using CH/EtOAc 7:3 to obtain a colorless oil (456 mg, 92%).

HPLC: 4.386 min.

Step III: 6-Hydroxymethyl-benzo[1,4]oxazine-4-carboxylic acid tert-butylester Step IV: 6-Formyl-benzo[1,4]oxazine-4-carboxylic acid tert-butylester

Step III and IV were carried out according to the synthesis ofintermediate 5.

HPLC: 3.388 min.

Intermediate 64:(6-Formyl-3-oxo-2,3-dihydro-benzo[14]oxazin-4-yl)-acetic acid methylester

Step I: Methyl-3-amino-4-hydroxybenzoate

To a solution of 3-amino-4-hydroxybenzoic acid (10 g, 0.65 mol) inmethanol (1.5 L) was added thionylchloride (233 g, 1.96 mol) drop-wiseat 5-10° C. with stirring and allowed to reflux at 65° C. for 16 h.Excess methanol and thionylchloride was distilled off and crudedissolved in ethylacetate (500 mL). The organic layer was washed with 5%aqueous NaHCO₃ solution, water, brine and dried. The solvent was removedunder vacuum to give methyl-3-amino-4-hydroxybenzoate (105 g, 95%).

Step II: Methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-carboxylate

To a mixture of methyl-3-amino-4-hydroxybenzoate (105 g, 0.62 mol) andbenzyltriethylammonium chloride (142 g, 0.62 mol) in dry CHCl₃ (1.5 L)was added NaHCO₃ (211 g, 2.5 mol) with stirring. The reaction mixturewas cooled to −5° C., added chloroacetylchloride (85 g, 0.75 mol) in dryCHCl₃ (350 mL) over a period of 1.5 h at the same temperature. Thereaction mixture was then heated to 55° C. for 16 h. The solvent wasremoved under vacuum, added water (3 L) and filtered off the solid. Thesolid product was dried and recrystallised from ethanol to givemethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-carboxylate (108 g, 83%).

Step III: 6-(Hydroxymethyl)-2H-1,4-benzoxazin-3(4H)-one

A solution of methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-carboxylate(30 g, 0.145 mol) in dry CH₂Cl₂ (500 mL) was cooled to −78° C. and addedDIBAL-H (51 g, 0.36 mol) over a period of 45 min and then stirred at thesame temperature for 14 h. The reaction mixture was quenched with 1.5NHCl and filtered off the solid product. The solid compound was driedunder vacuum to give 6-(hydroxymethyl)-2H-1,4-benzoxazin-3(4H)-one (18g, 69%).

Step IV: TBDMS-6-(hydroxymethyl)-2H-1,4-benzoxazin-3(4H)-one

To a solution of 6-(hydroxymethyl)-2H-1,4-benzoxazin-3(4H)-one (18 g,0.1 mol) in dry DMF (250 mL) was added imidazole (13.7 g, 0.2 mol) andstirred at 0° C. for 30 min. To the above reaction mixture was addedTBDMSiCl (23 g, 0.15 mol) in portions and stirred at RT for 4 h. Thereaction mixture was diluted with water and filtered off the solidobtained. The solid was dried under vacuum to giveTBDMS-6-(hydroxymethyl)2H-1,4-benzoxazin-3(4H)-one (24.5 g, 83%).

Step V:Methyl-[6-(hydroxymethyl)-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]acetate

To a suspension of NaH (0.3 g, 0.01 mol) in dry DMF (15 mL) was addedTBDMS-6-(hydroxymethyl)₂H-1,4-benzoxazin-3(4H)-one (2 g, 0.0068 mol) at0° C. with stirring and allowed to stir at RT for 2 h. The reactionmixture was cooled to 0° C., added methylchloroacetate (1 g, 0.0088 mol)and stirred at RT for 12 h. The reaction mixture was further cooled to0° C., added 50 mL of 1.5N HCl solution and stirred at RT for 12 h. Thereaction mixture was diluted with water (200 mL), extracted withethylacetate (3×150 mL). The combined organic layer was washed with 10%aqueous NaHCO₃ solution, brine and dried. The solvent was removed undervacuum and crude purified by column chromatography over silica gel(CHCl₃/Methanol, 99.5:0.5) to givemethyl-[6-(hydroxymethyl)-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]acetate(1.2 g, 70%).

Step VI:Methyl-[6-(Formyl)-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]acetate

A mixture of PCC (4.2 g, 0.019 mol) and celite (4 g) in dry CH₂Cl₂ (100mL) was cooled to 0° C. and slowly added a solution ofmethyl-[6-(hydroxymethyl)-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]acetate(1.2 g, 0.0048 mol) in CH₂Cl₂ (30 mL) under N₂. The reaction mixture wasstirred at RT for 2 h, passed through celite, washed with CH₂Cl₂ (50 mL)and concentrated to give crude product, which was purified on silica gelaffording 1.05 g (87%).

LC-MS: M/Z ESI: 1.15 min, 250.41 (M+1). ¹H NMR (DMSO-d6) δ 9.88 (s, 1H),7.65-7.60 (m, 2H), 7.24 (d, J=8.1 Hz, 1H), 4.85 (d, J=9.9 Hz, 4H), 3.71(s, 3H).

Intermediate 65:4-Butyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbaldehyde

This intermediate was synthesized according to the synthesis ofintermediate 2. Overall yield 33%.

LC-MS: M/Z ESI: 1.60 min, 234.35 (M+1). ¹H NMR (DMSO-d6) δ 7.66 (d,J=0.7 Hz, 1H), 7.58 (dd, J=1.7 Hz, 8.1 Hz, 1H), 7.18 (d, J=8.2 Hz, 1H),4.77 (s, 2H), 3.96 (t, J=7.3 Hz, 1H), 1.61-1.51 (m, 3H), 1.97-1.27 (m,3H), 0.91 (t, J=7.3 Hz, 3H).

Intermediate 66:4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbaldehyde

This intermediate was synthesized according to the synthesis ofintermediate 2. Overall yield 29%.

¹H NMR (DMSO-d6) δ 9.78 (s, 1H), 7.58 (dd, J=1.5 Hz, 7.9 Hz, 1H), 7.47(d, J=1.9 Hz, 7.40-7.18 (m, 6H), 5.22 (s, 2H), 4.95 (s, 2H), 3.3 (d,J=7.2 Hz, 1H).

Intermediate 67: 2-Chloro-5-[1,3]dioxolan-2-yl-benzofuran

Step I: 5-[1,3]Dioxolan-2-yl-benzofuran

A mixture of benzofuran-5-carbaldehyde (150 mg, 1.03 mmol), ethyleneglycol (230 ul, 4 eq), trimethyl orthoformate (123 ul, 1.1 eq) andtetrabutylammonium tribromide (49 mg, 0.1 eq) was stirred at roomtemperature for one night. Some starting material could be detected byTLC. However, the reaction mixture was poured into saturated NaHCO₃solution and the product was extracted with ethyl acetate. Combinedorganic layers were dried over anhydrous sodium sulfate, filtrated andconcentrated to give a crude product, which was purified by flashchromatography using cyclohexane/ethyl acetate 20:0.75 as solvents. Thetitle compounds was obtained in 36% yield (70 mg).

LC-MS: M/Z ESI: 1.51 min, 191.30 (M+1).

Step II: 2-Chloro-5-[1,3]dioxolan-2-yl-benzofuran

5-[1,3]Dioxolan-2-yl-benzofuran (50 mg, 0.26 mmol) was dissolved in TIE(2 mL) and the solution was cooled down to −78° C. Butyl lithium (180uL, 1.1 eq.) was added dropwise. This mixture was stirred 30 min at 25°C. Then the reaction mixture was cooled down to −78° C. and NCS (39 mg,1.1 eq.) dissolved in 1 mL THF was added dropwise to the reactionmixture. After 1 h30 at −78° C. only small amount of starting materialcould be detected. The temperature was increased slowly to roomtemperature overnight. Water and ethyl acetate were added to the mixtureand the aqueous layer was extracted 3 times. Combined organic phases wasdried over MgSO₄, filtrated and evaporated to give2-Chloro-5-[1,3]dioxolan-2-yl-benzofuran (48.1 mg, 81%) sufficientlypure to be used in the next step.

LC-MS: M/Z ESI: 1.77 min, 225.23 (M+1).

Intermediate 68: 3-Amino-benzo[d]isoxazole-5-carbaldehyde

Kaiser oxime resin (Novabiochem 01-64-0188) (250 mg) was washed with DCMand THF (3 times 5 min), 2 ml of THF was added followed by the additionof 300 ul of potassium-tert.butoxide (1M in THF, 1.2 eq.) at r.t. Theresin turned orange and was shaken in the Quest210™ for 15′.2-Fluoro-5-formyl-benzonitrile (75 mg, 2 eq.) in 1 ml THF was added andthe reaction was heated at 55° C. for 12 h. The resin was washed withDCM, MeOH, water (each 2×5 minutes) and MeOH (4×5 min). The resin wasdried at 40° C. with a flow of Argon for 30′ before cleaving.

The so dried resin was treated with TFA/5N HCl 4:1 (2.5 ml) for 2 h at55° C. The solution was collected in 20 ml vials and the resin waswashed twice with 4 ml of DCM. The collected fractions were evaporatedwith the Genevac HT4 to dryness affording: 37 mg (92%) of pure3-Amino-benzo[d]isoxazole-5-carbaldehyde.

HPLC: 1.47 min. LC-MS: M/Z ESI: 0.82 min, 163.26 (M+1).

Intermediate 69: 4-Piperidin-1-yl-quinazoline-6-carboxylic acid methylester

This intermediate was prepared according to the synthesis ofintermediate 8 starting from 4-Chloro-quinazoline-6-carboxylic acidmethyl ester (intermediate 7).

HPLC: 1.81 min. LC-MS: M/Z ESI: 1.78 min, 272.32 (M+1).

Intermediate 70: 4-Piperidin-1-yl-quinazoline-6-carbaldehyde

This intermediate was prepared according to the synthesis ofintermediate 5 starting from 4-Piperidine-quinazoline-6-carboxylic acidmethyl ester (intermediate 71).

HPLC: 1.36 min. LC-MS: M/Z ESI: 1.40 min, 242.32 (M+1).

Intermediate 71: 3-(5-Formyl-benzofuran-3-yl)-propionic acid ethyl ester

100 mg of 3-(5-Formyl-benzofuran-3-yl)-acrylic acid ethyl ester(intermediate 62) were dissolved in EtOAc in the presence of Palladiumon charcoal and Argon. To this was connected a H₂-balloon andhydrogenation was carried out for 12 h. The palladium was filtered offand the solvents were evaporated affording pure title compound (80 mg,80%).

HPLC: 3.53 min. LC-MS: M/Z ESI: 1.68 min, 247.25 (M+1).

Intermediate 72: 2-Methyl-5-[1,3]dioxolan-2-yl-benzofuran

5-[1,3]Dioxolan-2-yl-benzofuran (50 mg, 0.26 mmol) was dissolved in THF(2 mL) and the solution was cooled down to −78° C. Butyl lithium (180uL, 1.1 eq.) was added dropwise. This mixture was stirred 30 min at 25°C. Then the reaction mixture was cooled down to −78° C. and iodomethane(18.1 uL, 1.1 eq.) dissolved in 1 mL THF was added dropwise to thereaction mixture. The temperature was increased slowly to roomtemperature overnight. Despite some starting material was detected,water and ethyl acetate were added to the mixture and the aqueous layerwas extracted 3 times. Combined organic phases was dried over MgSO₄,filtrated and evaporated to give2-methyl-5-[1,3]dioxolan-2-yl-benzofuran (41.2 mg, 70%) sufficientlypure to be used in the next step.

LC-MS: M/Z ESI: 1.71 min, 205.34 (M+1).

Intermediate 73: 5-[1,3]Dioxolan-2-yl-benzofuran-2-carboxylic acidmethyl ester

5-[1,3]Dioxolan-2-yl-benzofuran (50 mg, 0.26 mmol) was dissolved in THF(2 mL) and the solution was cooled down to −78° C. Butyl lithium (180uL, 1.1 eq.) was added dropwise. This mixture was stirred 30 min at 25°C. Then the reaction mixture was cooled down to −78° C. and methylcyanoformate (23 uL, 1.1 eq.) dissolved in 1 mL THF was added dropwiseto the reaction mixture. After 1 h30 only small amount of startingmaterial was detected and two major compounds were formed (expectedproduct/dimer 73:27). The temperature was increased slowly to roomtemperature overnight. Water and ethyl acetate were added to the mixtureand the aqueous layer was extracted 3 times. Combined organic phases wasdried over MgSO₄, filtrated and evaporated to give the5-[1,3]Dioxolan-2-yl-benzofuran-2-carboxylic acid methyl ester (31.9 mg,44%) mixed with the dimer (expected product/dimer 46:54). The mixturewas used directly in the next step.

LC-MS: M/Z ESI: 1.54 min, 249.26 (M+1) and 1.88 min, 407.20 (M+1,Dimer).

Intermediate 74: 3-Bromo-2-fluoro-benzofuran-5-carbaldehyde

Benzofuran-5-carbaldehyde (100 mg, 0.68 mmol) in ether (1 mL) was addedto a cold solution (−78° C.) of NBS (158 mg, 1.3 eq) and pyridiniumpoly(hydrogen fluoride) 70% (0.850 mL) in ether (4 mL) in apolypropylene tube. The reaction was allowed to warm up to roomtemperature overnight. The reaction mixture was poured into ice waterand extracted with ether. The ether phase was washed with aqueousbicarbonate, dried over sodium sulfate, filtrated and evaporated to give3-bromo-2-fluoro-benzofuran-5-carbaldehyde (141.6 mg). It was purifiedon reverse phase HPLC (solvents gradient H₂O/CH₃CN 0.1% TFA) affordingthe title compound (62 mg, 37%), which was used in the next step.

LC-MS: M/Z ESI: 1.56 min. HPLC=3.11 min (99.34%). ¹H NMR: (DMSO-d6) δ9.94 (s, 1H), 8.09 (d, 1H, ³J=1.8 Hz), 7.99 (dd, 1H, ³J=8.4, 1.8 Hz),7.38 (d, 1H, ³J=8.4 Hz), 6.87 (d, 1H, ²J_(H-F)=59 Hz), 6.01 (d, 1H,³J_(H-F)=15.1 Hz). ¹⁹F NMR: (DMSO-d6) δ-114.80, −114.88.

Intermediate 75: 2-Fluoro-5-[1,3]dioxolan-2-yl-benzofuran

5-[1,3]Dioxolan-2-yl-benzofuran (50 mg, 0.26 mmol) was dissolved in THF(2 mL) and the solution was cooled down to −78° C. Butyl lithium (180uL, 1.1 eq.) was added dropwise. This mixture was stirred 30 min at 25°C. Then the reaction mixture was cooled down to −78° C. andN-fluorodibenzenesulfonamide (91 mg, 1.1 eq.), dissolved in 1 mL THF,was added dropwise to the reaction mixture. The mixture was stirredovernight between −78° C. and room temperature. Water and ethyl acetatewere added to the mixture and the aqueous layer was extracted 3 times.Combined organic phases was dried over MgSO₄, filtrated and evaporated,to give the 2-Fluoro-5-[1,3]dioxolan-2-yl-benzofuran (75 mg) mixed withside products. However it was sufficiently pure to be used for the nextstep.

The following examples have been synthesized:

Example 1 Preparation of5-(1,3-benzodioxol-5-ylmethylene)-1,3-thiazolidine-2,4-dione

In a 100 ml round bottom flask were placed 20 g of thiazolidine, 15.6 gof piperonal and 7.7 g of beta-alanine in 80 ml of acetic acid. Thereaction was stirred for 3 h at 100° C. and then slowly cooled to roomtemperature, while the desired condensation product crystallized. Thecrystals were filtered, washed with acetic acid (rt.) and water thanrecrystallized from DME (25 ml), affording 28 g (84%) of pure5-(1,3-benzodioxol-5-ylmethylene)-1,3-thiazolidine-2,4-dione. Thecorresponding potassium salt was obtained via the following route:5-(1,3-benzodioxol-5-ylmethylene)-1,3-thiazolidine-2,4-dione wassuspended in THF, followed by the addition of 1N solution of KOH inwater (1.0 eq.). A clear solution has been obtained, which uponlyophilization gave pure potassium salt of5-(1,3-benzodioxol-5-ylmethylene)-1,3-thiazolidine-2,4-dione.

HPLC: 3.48 min. LC-MS: M/Z ESI: 1.31 min, 248.12 (M−1). NMR (parent): ¹HNMR (DMSO-d6) δ 12.5 (br. s, 1H), 7.71 (s, 1H), 7.06-7.16 (m, 3H), 6.12(s, 2H).

In cases were the final compounds did not crystallize from the reactionsolutions, small quantities of water were added, leading to theprecipitation of the desired condensation product.

The crude either precipitated pure enough from the reaction mixture, orwas recrystallized from an appropriate solvent like DME, methanol, EtOAcor purified by flash-chromatography using EtOAc, cyclohexane mixtures aseluents.

Alternatively the final compounds could be synthesized in a parallelmanner according to the following protocol:

In a parallel synthesizer Quest 210™ was placed the correspondingaldehyde, to which was added a mixture of piperidine (17.9 mg/tube) and2,4-thiazolidinedione (49.2 mg/tube) in DME (2 ml/tube). The reactionswere stirred for 3 h at 120° C. and then cooled to room temperatureunder agitation. 2 ml of H₂O were added. Those compounds, whichprecipitated were filtered off via the lower manifold. The remainingclear solutions were reduced in volume, followed by the addition ofwater. The so formed solids were filtered and washed with little amountof DME, affording pure condensation products.

Example 2 Preparation of5-(1,3-benzodioxol-5-ylmethylene)-2-thioxo-1,3-thiazolidin-4-one

In a 24 ml vial was placed 1 g of commercially available rhodanine, 1.3g of piperonal and 0.5 ml of TEA in 10 ml of DME. The reaction wasstirred for 5 h at 120° C. and then cooled to room temperature uponwhich the final product precipitated. The solid was filtered and washedwith DME affording 1.6 g (80%) of orange powder.

LC-MS: M/Z ESI: 1.46 min, 266.00 (M+1), 264.08 (M−1). NMR (parent): ¹HNMR (DMSO-d6) δ 13.75 (br. s, 1H), 7.58 (s, 1H), 7.08-7.18 (m, 3H), 6.14(s, 2H).

Example 3 Preparation of5-(2,3-dihydro-1,4-benzodioxin-6-ylmethylene)-1,3-thiazolidine-2,4-dione

Following the general method as outlined in Example 1, starting from2,3-dihydro-1,4-benzodioxin-6-carbaldehyde and1,3-thiazolidine-2,4-dione, the title compound was obtained.

HPLC: 2.58 min. LC-MS: M/Z ESI: 1.32 min, 262.16 (M−1). ¹H NMR:(DMSO-d6) δ 12.52 (br. s, 1H), 7.68 (s, 1H,), 7.09 (dd, 2H, J=1.9, 7.1),7.00 (d, 1H, J=9.0 Hz), 4.36-4.22 (m, 4H).

Example 4 Preparation of5-(2,3-dihydro-1-benzofuran-5-ylmethylene-1,3-thiazolidine-2,4-dione

Following the general method as outlined in Example 1, starting from2,3-dihydro-1-benzofuran-5-carbaldehyde and 1,3-thiazolidine-2,4-dione,the title compound was obtained.

HPLC: 3.27 min. LC-MS: M/Z ESI: 1.37 min, 246.18 (M−1). ¹H NMR:(DMSO-d6) δ 9.80 (br. s, 1H), 7.37 (s, 1H,), 7.25 (d, 1H, J=8.3), 7.21(s, 1H), 6.80 (d, 1H, J=8.3 Hz), 4.54 (t, 2H, J=8.85), 3.19 (t, 2H,J=8.85)

Example 5 Preparation of5-[(7-methoxy-1,3-benzodioxol-5-yl)methylene]-1,3-thiazolidine-2,4-dione

Following the general method as outlined in Example 1, starting from7-methoxy-1,3-benzodioxol-5-yl)carbaldehyde and1,3-thiazolidine-2,4-dione, the title compound was obtained.

HPLC: 3.57 min. LC-MS: M/Z ESI: 1.30 min, 278.07 (M−1). ¹H NMR:(DMSO-d6) δ 12.63 (br. s, 1H), 7.78 (s, 1H,), 7.65 (s, 1H), 7.57 (d, 1H,J=8.5 Hz), 7.45 (dd, 2H, J=0.8, 7.6).

Example 6 Preparation of 5-[(9,10-dioxo-9,10-dihydroanthracen-2-ylmethylene]-1,3-thiazolidine-2,4-dione

Following the general method as outlined in Example 1, starting from(9,10-dioxo-9,10-dihydroanthracen-2-yl)carbaldehyde and1,3-thiazolidine-2,4-dione, the title compound was obtained.

HPLC: 4.12 min. LC-MS: M/Z ESI: 1.50 min, 334.09 (M−1).

Example 7 Preparation of(5-[(2,2-difluoro-1,3-benzodioxol-5-yl)methylene]-1,3-thiazolidine-2,4-dione

Following the general method as outlined in Example 1, starting from(2,2-difluoro-1,3-benzodioxol-5-yl)carbaldehyde and1,3-thiazolidine-2,4-dione, the title compound was obtained.

HPLC: 3.85 min. LC-MS (10 min.): M/Z ESI: 3.15 min, 284.11 (M−1). ¹HNMR: (DMSO-d6) δ 12.63 (br. s, 1H), 7.78 (s, 1H,), 7.65 (s, 1H), 7.57(d, 1H, J=8.5 Hz), 7.45 (dd, 2H, J=0.8, 7.6)

Example 8 Preparation of5-(1,3-dihydro-2-benzofuran-5-ylmethylene)-1,3-thiazolidine-2,4-dione

Following the general method as outlined in Example 1, starting from1,3-dihydro-2-benzofuran-5-carbaldehyde (intermediate 4) and1,3-thiazolidine-2,4-dione, the title compound was obtained.

HPLC: 2.89 min. LC-MS: M/Z ESI: 1.20 min, 246.20 (M−1). ¹H NMR:(DMSO-d6) δ 12.60 (br. s, 1H), 7.80 (s, 1H,), 7.56-7.42 (m, 2H), 5.03(s, 4H)

Example 9 Preparation of5-(1-benzofuran-5-ylmethylene)-1,3-thiazolidine-2,4-dione

Following the general method as outlined in Example 1, starting from1-benzofuran-5-carbaldehyde (intermediate 1) and1,3-thiazolidine-2,4-dione, the title compound was obtained.

HPLC: 3.54 min. LC-MS: M/Z ESI: 1.47 min, 244.20 (M−1). ¹H NMR:(DMSO-d6) δ 12.58 (br. s, 1H), 8.10 (d, 1H, J=2.2 Hz), 7.92 (s, 2H),7.74 (d, 1H, J=8.6 Hz), 7.57 (d, 1H, J=8.6 Hz), 7.07 (s, 1H)

Example 10 Preparation of5-[(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-ylmethylene]-1,3-thiazolidine-2,4-dione

Following the general method as outlined in Example 1, starting from[(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbaldehyde(intermediate 2) and 1,3-thiazolidine-2,4-dione, the title compound wasobtained.

HPLC: 2.79 min. LC-MS: M/Z ESI: 1.19 min, 289.22 (M−1). ¹H NMR:(DMSO-d6) δ 12.58 (br. s, 1H), 7.81 (s, 1H), 7.41 (s, 1H), 7.13-7.26 (d,2H), 4.74 (s, 2H), 2.99 (s, 3H)

Example 11 Preparation of5-(1,3-benzodioxol-5-ylmethylene)-2-imino-1,3-thiazolidine-4-one

Following the general method as outlined in Example 1, starting from1,3-benzodioxol-5-carbaldehyde and 2-imino-1,3-thiazolidin-4-one, thetitle compound was obtained.

HPLC: 2.29 min. LC-MS: M/Z ESI: 1.21 min, 247.25 (M−1).

Example 12 Preparation of5-Quinolin-6-ylmethylene-thiazolidine-2,4-dione

Following the general method as outlined in Example 1, starting fromquinoline-6-carbaldehyde (intermediate 5) and1,3-thiazolidine-2,4-dione, the title compound was obtained.

HPLC: 1.445 min. LC-MS: M/Z ESI: 1.17 min, 257.21 (M+1). ¹H NMR:(DMSO-d6) δ 8.88 (d, J=6 Hz, 1H), 8.40 (d, J=9 Hz, 1H), 8.07-7.90 (m,3H), 7.55 (q, J=6 Hz, 9 Hz, 1H), 7.45 (s, 1H).

Example 13 5-Quinolin-6-ylmethylene-2-thioxo-thiazolidin-4-one

Following the general method as outlined in Example 1, starting fromquinoline-6-carbaldehyde (intermediate 5) and rhodanine, the titlecompound was obtained.

HPLC: 2.05 min. LC-MS: M/Z ESI: 1.25 min, 273.14 (M+1). ¹H NMR:(DMSO-d6) δ 14.00 (br. s, 1H), 8.97 (d, J=2.3 Hz, 1H), 8.23 (d, J=9 Hz,1H), 8.10 (d, J=9 Hz, 1H), 7.95 (d, J=9 Hz, 1H), 7.79 (s, 1H), 7.61 (q,J=3 Hz, 9 Hz, 1H).

Example 14 2-Imino-5-quinolin-6-ylmethylene-thiazolidin-4-one

Following the general method as outlined in Example 1, starting fromquinoline-6-carbaldehyde (intermediate 5) and2-imino-1,3-thiazolidin-4-one, the title compound was obtained.

HPLC: 1.16 min. LC-MS: M/Z ESI: 1.10 min, 256.18 (M+1). ¹H NMR:(DMSO-d6) δ 12.58 (br. s, 1H), 8.84 (s, 1H), 8.37 (d, J=6 Hz, 1H),8.02-7.86 (m, 3H), 7.52 (q, J=6 Hz, 9 Hz, 1H), 7.26 (s, 1H), 7.02 (b. s,1H).

Example 155-(3-Methyl-benzo[d]isoxazol-5-ylmethylene)-thiazolidine-2,4-dione

Following the general method as outlined in Example 1, starting from3-Methyl-benzo[d]isoxazole-5-carbaldehyde (intermediate 6) and1,3-thiazolidine-2,4-dione, the title compound was obtained.

HPLC: 2.99 min. LC-MS: M/Z ESI: 1.30 min, 259.17 (M−1). ¹H NMR:(DMSO-d6) δ 12.58 (br. s, 1H), 8.08 (s, 1H), 7.95 (s, 1H), 7.85 (s, 2H),2.59 (s, 3H).

Example 16 5-(4-Phenyl-quinazolin-6-ylmethylene)-thiazolidine-2,4-dione

Following the general method as outlined in Example 1, starting from4-Phenyl-quinazoline-6-carbaldehyde (intermediate 13) and1,3-thiazolidine-2,4-dione, the title compound was obtained.

HPLC: 3.45 min. LC-MS: M/Z ESI: 1.25 min, 334.15 (M+1). ¹H NMR:(DMSO-d6) δ 12.74 (br. s, 1H), 9.43 (s, 1H), 8.24 (m, 2H), 8.00-7.86 (m,2H), 7.72-7.66 (m, 5H).

Example 175-(4-Dimethylamino-quinazolin-6-ylmethylene)-thiazolidine-2,4-dione

Following the general method as outlined in Example 1, starting from4-Dimethylamino-quinazoline-6-carbaldehyde (intermediate 14) and1,3-thiazolidine-2,4-dione, the title compound was obtained.

HPLC: 1.47 min. LC-MS: M/Z ESI: 1.26 min, 301.26 (M+1). ¹H NMR:(DMSO-d6) δ 8.81 (s, 1H), 8.54 (s, 1H), 8.16-7.95 (m, 3H), 7.13-7.26 (d,2H), 3.63 (s, 6H).

The following examples were synthesized as described in Example 1 and 17starting from intermediates 15 to 31 and 1,3-thiazolidine-2,4-dione

Intermediate# as starting Example material Compound name Mass (M + 1) 1816 5-[(4-aminoquinazolin-6-yl)methylene]-1,3- 273.29thiazolidine-2,4-dione 19 155-[(4-piperidin-1-ylquinazolin-6-yl)methylene]-1,3- 341.40thiazolidine-2,4-dione 20 225-[(4-morpholin-4-ylquinazolin-6-yl)methylene]- 343.201,3-thiazolidine-2,4-dione 21 175-{[4-(benzylamino)quinazolin-6-yl]methylene}- 363.101,3-thiazolidine-2,4-dione 22 215-{[4-(diethylamino)quinazolin-6-yl]methylene}- 329.301,3-thiazolidine-2,4-dione 23 185-({4-[(pyridin-2-ylmethyl)amino]quinazolin-6- 364.40yl}methylene)-1,3-thiazolidine-2,4-dione 24 195-({4-[(pyridin-3-ylmethyl)amino]quinazolin-6- 364.40yl}methylene)-1,3-thiazolidine-2,4-dione 25 23 ethyl1-{6-[(2,4-dioxo-1,3-thiazolidin-5- 413.20ylidene)methyl]quinazolin-4-yl}piperidine-3- carboxylate 26 25 ethyl1-{6-[(2,4-dioxo-1,3-thiazolidin-5- 413.30ylidene)methyl]quinazolin-4-yl}piperidine-4- carboxylate 27 24tert-butyl 1-{6-[(2,4-dioxo-1,3-thiazolidin-5- 427.20ylidene)methyl]quinazolin-4-yl}-L-prolinate 28 205-{[4-(4-methylpiperazin-1-yl)quinazolin-6- 356.13yl]methylene}-1,3-thiazolidine-2,4-dione 29 315-{[4-(4-pyrimidin-2-ylpiperazin-1-yl)quinazolin- 420.206-yl]methylene}-1,3-thiazolidine-2,4-dione 30 305-({4-[4-(4-fluorophenyl)piperidin-1-yl]quinazolin- 435.306-yl}methylene)-1,3-thiazolidine-2,4-dione 31 295-{[4-(4-benzylpiperidin-1-yl)quinazolin-6- 431.30yl]methylene}-1,3-thiazolidine-2,4-dione 32 285-({4-[4-(2-phenylethyl)piperidin-1-yl]quinazolin- 445.406-yl}methylene)-1,3-thiazolidine-2,4-dione 33 275-{[4-(4-methylpiperidin-1-yl)quinazolin-6- 355.20yl]methylene}-1,3-thiazolidine-2,4-dione 34 265-{[4-(4-hydroxypiperidin-1-yl)quinazolin-6- 357.40yl]methylene}-1,3-thiazolidine-2,4-dione

Example 351-[6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-quinazolin-4-yl]-piperidine-4-acid

50 mg of Ethyl1-{6-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]quinazolin-4-yl}piperidine-4-carboxylate(example 26) was dissolved in 2 ml solution of THF/water (1/1). A fewdrops of 5N NaOH were added, and the reaction was stirred for 12 h atrt. After completion of the reaction, solvents were evaporated andtitled compound was precipitated in diethylether as a yellow solid (40mg, 82%).

HPLC: 1.43 min. LC-MS: M/Z ESI: 1.15 min, 385.20 (M+1).

Example 361-[6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-quinazol-4-yl]-piperidine-3-carboxylicacid

Following the general method as outlined in Example 35, the titlecompound was obtained.

HPLC:1.50 min. LC-MS: M/Z ESI: 1.10 min, 385.40 (M+1).

Example 371-[6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-quinazolin-4-yl]-pyrrolidine-2-carboxylicacid

10 mg of tert-butyl1-{6-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]quinazolin-4-yl}-L-prolinate(example 27) was stirred in a 25% (TFA/DCM) solution for 12 h at rt. Thesolvents were evaporated under vacuo and expected compound wasprecipitated with diethyl ether to give pure1-[6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-quinazolin-4-yl]-pyrrolidine-2-carboxylicacid (7 mg, 81%).

HPLC: 1.43 min. LC-MS: M/Z ESI: 1.10 min, 371.30 (M+1).

Example 385-(4-Methylamino-quinazolin-6-ylmethylene)-thiazolidine-2,4-dione

Following the general method as outlined in Example 1, starting from4-methylamino-quinazoline-6-carbaldehyde (intermediate 11) and1,3-thiazolidine-2,4-dione, the title compound was obtained.

HPLC: 1.43 min. LC-MS: M/Z ESI: 1.03 min, 287.19 (M+1). ¹H NMR:(DMSO-d6) δ 11.97 (br. s, 1H), 8.53 (br. s, 2H), 8.37 (s, 1H), 7.92 (d,J=8 Hz, 1H), 7.76 (s, 2H), 3.03 (s, 3H)

Example 39 5-(4-Methoxy-quinazolin-6-ylmethylene)-thiazolidine-2,4-dione

Following the general method as outlined in Example. 1, starting from4-methoxy-quinazoline-6-carbaldehyde (intermediate 10) and1,3-thiazolidine-2,4-dione, the title compound was obtained.

HPLC: 2.57 min. LC-MS: M/Z ESI: 1.12 min, 288.20 (M+1). ¹H NMR:(DMSO-d6) δ 12.74 (br. s, 1H), 8.86 (s, 1H), 8.32 (s, 1H), 8.11 (m, 1H),8.03-7.98 (m, 2H), 4.18 (s, 3H)

Example 402-Imino-5-(4-methylamino-quinazolin-6-ylmethylene)-thiazolidin-4-one

Following the general method as outlined in Example 1, starting from4-methylamino-quinazoline-6-carbaldehyde (intermediate 11) and2-imino-1,3-thiazolidin-4-one, the title compound was obtained.

HPLC: 2.43 min. LC-MS: M/Z ESI: 1.07 min, 286.14 (M+1).

Example 412-Imino-5-(4-piperidine-quinazolin-6-ylmethylene)-thiazolidin-4-one

Following the general method as outlined in Example 1, starting from4-piperidine-quinazoline-6-carbaldehyde (intermediate 72) and2-imino-1,3-thiazolidin-4-one, the title compound was obtained.

HPLC: 1.78 min. LC-MS: M/Z ESI: 1.40 min, 340.26 (M+1). ¹H NMR:(DMSO-d6) δ 8.76 (s, 1H), 8.18 (s, 1H), 8.16 (d, J=6 Hz, 1H), 7.88 (d,J=9 Hz, 1H), 7.80 (s, 1H), 4.09 (s, 4H), 1.80 (s, 6H).

Example 422-Imino-5-(4-dimethylamino-quinazolin-6-ylmethylene)-thiazolidin-4-one

Following the general method as outlined in Example 1, starting from4-piperidine-quinazoline-6-carbaldehyde (intermediate 14) and2-imino-1,3-thiazolidin-4-one, the title compound was obtained.

HPLC: 1.32 min. LC-MS (10 min.): M/Z ESI: 1.54 min, 300.23 (M+1). ¹HNMR: (DMSO-d6) δ 8.82 (s, 1H), 8.53 (s, 1H), 8.16 (d, J=9 Hz, 1H), 7.87(t, J=9 Hz, 2H), 3.65 (s, 6H).

Example 435-(2-Methyl-2H-benzotriazol-5-ylmethylene)-thiazolidine-2,4-dione

Following the general method as outlined in Example 1, starting from2-Methyl-2H-benzotriazole-5-carbaldehyde (intermediate 33) andthiazolidinedione, the title compound was obtained.

HPLC: 2.68 min. ¹H NMR: (DMSO-d6) δ 12.58 (br. s, 1H), 7.98 (s, 1H),7.92 (d, J=9 Hz, 1H), 7.62 (d, J=6 Hz, 1H), 7.43 (s, 1H), 4.48 (s, 3H).

Example 445-(3-Methyl-3H-benzotriazol-5-ylmethylene)-thiazolidine-2,4-dione

Following the general method as outlined in Example 1, starting from3-Methyl-3H-benzotriazole-5-carbaldehyde (intermediate 34) andthiazolidinedione, the title compound was obtained.

HPLC: 2.35 min. LC-MS: M/Z ESI: 1.22 min, 259.23 (M−1). ¹H NMR:(DMSO-d6) δ 12.58 (br. s, 1H), 8.17 (d, J=9 Hz, 1H), 8.07 (s, 1H), 7.62(d, J=6 Hz, 1H), 7.47 (s, 1H), 4.33 (s, 3H).

Example 455-(3-Ethyl-3H-benzimidazol-5-ylmethylene)-thiazolidine-2,4-dione

5(4-Amino-3-ethylamino-benzylidene)-thiazolidine-2,4-dione (50 mg, 0.19mmol) (intermediate 36) was dissolved in formic acid (5 mL) and thesolution stirred at 100° C. over night. Formic acid was then removed invacuo. The crude residue was then purified by silica gel column to givethe title compound (35 mg, 63%).

HPLC: 1.71 min. LC-MS: M/Z ESI: 0.82 min, 274.21 (M+1).

The following examples were synthesized as described in Example 45starting from intermediates 37 to 54 and 1,3-thiazolidine-2,4-dione.

Intermediate# as starting Example material Compound name Mass(M + 1) 4637 5-{[1-(4-phenylbutyl)-1H-benzimidazol-6- 378.30yl]methylene}-1,3-thiazolidine-2,4-dione 47 505-[(1-prop-2-yn-1-yl-1H-benzimidazol-6- 284.24yl)methylene]-1,3-thiazolidine-2,4-dione 48 385-[(1-{2-[4-(trifluoromethyl)phenyl]ethyl}-1H- 418.17benzimidazol-6-yl)methylene]-1,3-thiazolidine-2,4- dione 49 395-({1-[2-(4-hydroxyphenyl)ethyl]-1H-benzimidazol- 366.266-yl}methylene)-1,3-thiazolidine-2,4-dione 50 40 methyl4-{6-[(2,4-dioxo-1,3-thiazolidin-5- 386.35ylidene)methyl]-1H-benzimidazol-1- yl}cyclohexanecarboxylate 51 415-({1-[2-(5-methoxy-1H-indol-3-yl)ethyl]-1H- 419.21benzimidazol-6-yl}methylene)-1,3-thiazolidine-2,4- dione 52 425-({1-[(1-methyl-1H-pyrazol-4-yl)methyl]-1H- 340.99benzimidazol-6-yl}methylene)-1,3-thiazolidine-2,4- dione 53 435-({1-[2-(3,4-dimethoxyphenyl)ethyl]-1H- 410.37benzimidazol-6-yl}methylene)-1,3-thiazolidine-2,4- dione 54 545-({1-[2-(4-phenoxyphenyl)ethyl]-1H- 442.51benzimidazol-6-yl}methylene)-1,3-thiazolidine-2,4- dione 55 445-({1-[4-(trifluoromethyl)benzyl]-1H-benzimidazol- 404.166-yl}methylene)-1,3-thiazolidine-2,4-dione 56 454-{6-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]- 372.181H-benzimidazol-1-yl}cyclohexanecarboxylic acid 57 465-[(1-isobutyl-1H-benzimidazol-6-yl)methylene]- 302.251,3-thiazolidine-2,4-dione 58 475-({1-[2-(1,3-benzodioxol-4-yl)ethyl]-1H- 394.27benzimidazol-6-yl}methylene)-1,3-thiazolidine-2,4- dione 59 485-({1-[2-(2-phenoxyphenyl)ethyl]-1H- 442.29benzimidazol-6-yl}methylene)-1,3-thiazolidine-2,4- dione 60 495-{[1-(3,3-diphenylpropyl)-1H-benzimidazol-6- 440.27yl]methylene}-1,3-thiazolidine-2,4-dione 61 515-{[1-(2-methoxybenzyl)-1H-benzimidazol-6- 366.33yl]methylene}-1,3-thiazolidine-2,4-dione 62 525-{[1-(3-furylmethyl)-1H-benzimidazol-6- 326.24yl]methylene}-1,3-thiazolidine-2,4-dione 63 535-[(1-propyl-1H-benzimidazol-6-yl)methylene]-1,3- 288.18thiazolidine-2,4-dione

Example 64 5-Quinoxalin-6-ylmethylene-thiazolidine-2,4-dione

Following the general method as outlined in Example 1, starting fromquinoxaline-6-carbaldehyde (intermediate 55) and thiazolidinedione, thetitle compound was obtained.

HPLC: 2.48 min. LC-MS: M/Z ESI: 1.01 min, 256.20 (M−1). ¹H NMR:(DMSO-d6) δ 12.58 (br. s, 1H), 8.93 (d, J=9 Hz, 2H), 8.18 (s, 1H), 8.10(d, J=9 Hz, 1H), 8.03 (d, J=9 Hz, 1H), 7.51 (s, 1H).

Example 65 5-Quinoxalin-6-ylmethylene-2-thioxo-thiazolidin-4-one

Following the general method as outlined in Example 1, starting fromquinoxaline-6-carbaldehyde (intermediate 55) and rhodanine, the titlecompound was obtained.

HPLC: 3.10 min. LC-MS: M/Z ESI: 1.17 min, 272.13 (M−1). ¹H NMR:(DMSO-d6) δ 12.00 (br. s, 1H), 9.02 (s, 2H), 8.31 (s, 1H), 8.21 (d, J=9Hz, 1H), 8.04 (d, J=9 Hz, 1H), 7.90 (s, 1H)

Example 66 2-Imino-5-quinoxalin-6-ylmethylene-thiazolidin-4-one

Following the general method as outlined in Example 1, starting fromquinoxaline-6-carbaldehyde (intermediate 55) and2-imino-1,3-thiazolidin-4-one, the title compound was obtained.

HPLC: 1.97 min. LC-MS: M/Z ESI: 1.02 min, 255.19 (M−1). ¹H NMR:(DMSO-d6) δ9.57-9.30 (b. d, J=81 Hz, 2H), 9.00 (s, 2H), 8.26-8.07 (m,3H), 7.84 (s, 1H).

Example 67 5-Benzothiazol-6-ylmethylene-thiazolidine-2,4-dione

Following the general method as outlined in Example 1, starting fromquinoxaline-6-carbaldehyde (intermediate 56) and thiazolidinedione, thetitle compound was obtained.

HPLC: 2.85 min. LC-MS: M/Z ESI: 1.06 min, 261.11 (M−1). ¹H NMR:(DMSO-d6) δ 12.58 (br. s, 1H), 9.39 (s, 1H), 8.27 (s, 1H), 8.11 (d, J=9Hz, 1H), 7.70 (d, J=9 Hz, 1H), 7.42 (s, 1H).

Example 68 5-(3-Methyl-benzofuran-5-ylmethylene)-thiazolidine-2,4-dione

Following the general method as outlined in Example 1, starting from3-Methyl-benzofuran-5-carbaldehyde (intermediate 57) and1,3-thiazolidine-2,4-dione, the title compound was obtained.

HPLC: 1.47 min. LC-MS: M/Z ESI: 1.15 min, 257.21 (M−1). ¹H NMR:(DMSO-d6) δ 12.50 (br. s, 1H), 8.87 (d, J=6 Hz, 1H), 8.38 (d, J=9 Hz,1H), 8.07 (t, J=12 Hz, 2H), 7.92 (d, J=9 Hz, 1H), 7.53 (q, J=6 Hz, 12Hz, 1H), 7.45 (s, 1H).

Example 695-(2-Bromo-3-methyl-benzofuran-5-ylmethylene)-thiazolidine-2,4-dione

In a 25 ml 3 neck flask was placed5-(3-methyl-benzofuran-5-ylmethylene)-thiazolidine-2,4-dione (100 mg,0.39 mmol) (example 68) and Br2 (20 ul, 1 eq.) in 2 ml of AcOH at 0° C.The mixture was allowed to warm to room temperature. After 2 h at roomtemperature another equivalent of Br₂ was added. After 3 h the reactionwas filtered off to obtain a yellow product being the title compound (87mg, 66%).

LC-MS: M/Z ESI: 1.69 min, 339.8 (M+1). ¹H NMR: (DMSO-d6) δ12.50 (br. s,1H), 7.93 (s, 1H), 7.82 (s, 1H), 7.72 (d, J=6 Hz, 1H), 7.54 (d, J=6 Hz,1H), 2.20 (s, 3H).

Example 70 5-(3-bromo-benzofuran-5-ylmethylene)-thiazolidine-2,4-dione

Following the general method as outlined in Example 1, starting from3-Bromo-benzofuran-5-carbaldehyde (intermediate 58) and1,3-thiazolidine-2,4-dione, the title compound was obtained.

HPLC: 3.92 min. LC-MS: M/Z ESI: 1.57 min, 325.17 (M+1). ¹H NMR:(DMSO-d6) δ 12.60 (br. s, 1H), 8.42 (s, 1H), 8.00 (s, 1H), 7.85 (d, J=23Hz, 1H), 7.76 (s, 1H), 7.63 (d, J=23 Hz, 1H).

Example 713-[5-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-benzofuran-3-yl]-acrylicacid ethyl ester

Following the general method as outlined in Example 1, starting from3-(5-Formyl-benzofuran-3-yl)-acrylic acid ethyl ester (intermediate 60)and 1,3-thiazolidine-2,4-dione, the title compound was obtained.

HPLC: 4.00 min. LC-MS: M/Z ESI: 1.60 min, 342.20 (M−1). ¹H NMR:(DMSO-d6) δ 12.50 (br. s, 1H), 8.63 (s, 1H), 8.42 (s, 1H), 8.08 (s, 1H),7.83 (m, 2H), 7.62 (s, 1H), 4.22 (q, J=6 Hz, 9 Hz, 2H), 1.28 (t, J=9 Hz,3H).

Example 723-[5-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-benzofuran-3-yl]-acrylicacid

3-[5-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-benzofuran-3-yl]-acrylicacid ethyl ester (205 mg, 0.6 mmol) (example 71) were dissolved inTHF/water 4:2. To this solution was added under stirring 81 mg (4 eq.)of LiOH.H₂O. The reaction was stirred for 15 h. The solvents wereevaporated, and the residue was precipitated with ether. The solid waswashed with 1NHCl and dried to afford 170 mg (90%) of pure3-[5-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-benzofuran-3-yl]-acrylicacid.

HPLC: 3.25 min. LC-MS: M/Z ESI: 1.01 min, 314.11 (M−1). ¹H NMR:(DMSO-d6) δ 8.22 (s, 1H), 8.03 (s, 1H), 7.58 (dd, J=9 Hz, 33 Hz, 2H),7.43 (s, 1H), 7.25 (d, J=118 Hz, 1H), 7.07 (s, 1H).

Example 735-[3-(3-Oxo-3-piperidin-1-yl-propenyl)-benzofuran-5-ylmethylene]-thiazolidine-2,4-dione

180 mg (0.57 mmol) of3-[5-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-benzofuran-3-yl]-acrylicacid (example 72) was suspended in THF (25 ml). To this suspension wasadded DIEA (2 eq.) and piperidine (3 eq.). Under stirring was addedPyBOP (1.5 eq.). After 30 min the reaction mixture became clear, afteran additional 1 h a precipitate was formed. The reaction was stirredovernight. The precipitate was filtered off and washed with THF and 1NHCl affording the title compound in high purity.

HPLC: 3.91 min. LC-MS: M/Z ESI: 1.58 min, 383.22 (M+1). ¹H NMR:(DMSO-d6) δ 8.46 (s, 1H), 8.19 (s, 1H), 7.71-7.51 (m, 4H), 7.23 (d, J=15Hz, 1H), 3.73 (d, J=48 Hz, 2H), 1.51 (d, J=36 Hz, 3H).

The following amides were synthesized according to the synthesis ofexample 73.

Amine as starting Example material Compound name Mass(M + 1) 74 Proline-Methyl 1-((3-{5-[(2,4-dioxo-1,3-thiazolidin-5- 427.15 methylesterylidene)methyl]-1-benzofuran-3-yl}prop-2- enoyl)prolinate 75 D-proline-Methyl 1-((3-{5-[(2,4-dioxo-1,3-thiazolidin-5- 413.15 methylesterylidene)methyl]-1-benzofuran-3-yl}prop-2- enoyl)-D-prolinate 76Pyrollidine (5-({3-[(3-oxo-3-pyrrolidin-1-ylprop-1-en-1- 369.52yl]-1-benzofuran-5-yl}methylene)-1,3- thiazolidine-2,4-dione 77Morpholine 5-({3-[3-morpholin-4-yl-3-oxoprop-1-en-1-yl]- 385.071-benzofuran-5-yl}methylene)-1,3-thiazolidine- 2,4-dione 78 L-proline-Methyl 1-(3-{5-[(2,4-dioxo-1,3-thiazolidin-5- 427.13 methylesterylidene)methyl]-1-benzofuran-3-yl}prop-2- enoyl)-L-prolinate 79N-methyl- N-cyclohexyl-3-{5-[(2,4-dioxo-1,3-thiazolidin- 411.12cyclohexylamine 5-ylidene)methyl]-1-benzofuran-3-yl}-N- methylacrylamide80 N-ethyl- 3-{5-[(2,4-dioxo-1,3-thiazolidin-5- 387.10 hydroxyethyl-ylidene)methyl]-1-benzofuran-3-yl}-N-ethyl-N- amine(2-hydroxyethyl)acrylamide 81 CyclobutylamineN-cyclobutyl-3-{5-[(2,4-dioxo-1,3-thiazolidin- 369.135-ylidene)methyl]-1-benzofuran-3- yl}acrylamide 82 Azetidine5-({3-[3-azetidin-1-yl-3-oxoprop-1-en-1-yl]-1- 355.64benzofuran-5-yl}methylene)-1,3-thiazolidine- 2,4-dione 831,3-dihydro-2H- 5-({3-[3-(1,3-dihydro-2H-isoindol-2-yl)-3- 415.00isoindole oxoprop-1-en-1-yl]-1-benzofuran-5- (M − 1)yl}methylene)-1,3-thiazolidine-2,4-dione 84 Azepan5-({3-[3-azepan-1-yl-3-oxoprop-1-en-1-yl]-1- 397.46benzofuran-5-yl}methylene)-1,3-thiazolidine- 2,4-dione 85 Piperidin-1-3-{5-[(2,4-dioxo-1,3-thiazolidin-5- 398.00 ylamineylidene)methyl]-1-benzofuran-3-yl}-N- piperidin-1-ylacrylamide 86Pyridin-3-yl- 3-{5-[(2,4-dioxo-1,3-thiazolidin-5- 406.10 methylamineylidene)methyl]-1-benzofuran-3-yl}-N- (pyridin-3-ylmethyl)acrylamide 87Cyclohexylamine N-cyclohexyl-3-{5-[(2,4-dioxo-1,3-thiazolidin- 397.085-ylidene)methyl]-1-benzofuran-3- yl}acrylamide 88 4-N-methyl-5-({3-[3-(4-methylpiperazin-1-yl)-3-oxoprop-1- 398.02 piperazineen-1-yl]-1-benzofuran-5-yl}methylene)-1,3- thiazolidine-2,4-dione 89Cycloheptylamine N-cycloheptyl-3-{5-[(2,4-dioxo-1,3-thiazolidin- 411.445-ylidene)methyl]-1-benzofuran-3- yl}acrylamide 90 Pyroline5-({3-[3-(2,5-dihydro-1H-pyrrol-1-yl)-3- 367.11oxoprop-1-en-1-yl]-1-benzofuran-5-yl}methylene)-1,3-thiazolidine-2,4-dione 91 CyclopentylamineN-cyclopentyl-3-{5-[(2,4-dioxo-1,3-thiazolidin- 383.115-ylidene)methyl]-1-benzofuran-3- yl}acrylamide

Example 923-[5-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-benzofuran-3-yl]-propionicacid ethyl ester

Following the general method as outlined in Example 1, starting from3-(5-Formyl-benzofuran-3-yl)-propionic acid ethylester (intermediate 71)and 1,3-thiazolidine-2,4-dione, the title compound was obtained.

HPLC: 3.94 nm. LC-MS: M/Z ESI: 2.87 min, 346.15 (M+1). ¹H NMR: (DMSO-d6)δ 12.58 (br. s, 1H), 7.92 (d, J=6 Hz, 3H), 7.72 (d, J=9 Hz, 1H), 7.53(d, J=9 Hz, 1H), 4.03 (q, J=9 Hz, 15 Hz, 2H), 2.94 (t, J=9 Hz, 2H), 2.73(t, J=6 Hz, 2H), 1.14 (t, J=6 Hz).

Example 933-[5-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-benzofuran-3-yl]-propionicacid

The title compound was obtained applying standard saponificationstechniques as described for example 72 using example 92 as startingmaterial.

HPLC: 3.09 min. LC-MS (10 min.): M/Z ESI: 1.19 min, 316.14 (M−1). ¹HNMR: (DMSO-d6) δ 12.58 (br. s, 1H), 12.22 (b. s, 1H), 7.93 (d, J=12 Hz,3H), 7.70 (d, J=9 Hz, 1H), 7.54 (d, J=9 Hz, 1H), 2.91 (t, J=9 Hz, 2H),2.65 (t, 6 Hz, 2H).

Example 945-[3-(3-Oxo-3-piperidin-1-yl-propyl)-benzofuran-5-ylmethylene]-thiazolidine-2,4-dione

The title compound was obtained applying the synthetic protocol asdescribed for example 73 using example 93 as starting material.

HPLC: 3.783 min. LC-MS: M/Z ESI: 1.46 min, 385.14 (M+1). ¹H NMR:(DMSO-d6) δ 12.66 (br. s, 1H), 8.06 (s, 3H), 8.01 (s, 1H), 7.79 (s, 1H),3.50-1.60 (m, 14H).

Example 956-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-2,3-dihydro-benzo[1,4]oxazine-4-carboxylicacid tert-butyl ester

Following the general method as outlined in Example 1, starting from6-Formyl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butylester (intermediate 62) and 1,3-thiazolidine-2,4-dione, the titlecompound was obtained.

HPLC: 2.52 min. LC-MS: M/Z ESI: min, 261.21 (M-Boc-1).

Example 965-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethylene)-thiazolidine-2,4-dione

100 mg of 6-Formyl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acidtert-butyl ester (intermediate 62) were treated with TFA/DCM 25% for 2h. The solvents were evaporated to dryness and the remaining crude wasused for the Knoevenagel reaction as outlined in Example 1 withoutfurther purification to obtain the title compound as yellow solid.

HPLC: 2.56 min. LC-MS: M/Z ESI: 1.14 min, 261.24 (M−1). ¹H NMR:(DMSO-d6) δ 12.58 (br. s, 1H), 7.57 (s, 1H), 6.78 (s, 3H), 4.17 (t, J=3Hz, 2H), 3.28 (t, J=6 Hz, 2H).

Example 975-(4-Benzoyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethylene)-thiazolidine-2,4-dione

5-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethylene)-thiazolidine-2,4-dione(example 96) (35 mg, 0.13 mmol) in 4 ml anhydrous THF were treated withbenzoylchloride (156 uL, 10 eq.) in the presence of DIEA (2 eq.) for 3h. Excess of benzoylchloride was hydrolysed, EtOAc was added and theorganic phase was washed with NaHCO₃ and brine. The crude was purifiedon silica gel using EtOAc/cyclohexane 3:7 as eluent affording 14 mg(35%) of the title compound.

HPLC: 4.57 min. LC-MS: M/Z ESI: 2.11 min, 364.91 (M−1).

The following example was synthesized in the same way as described forexample 97.

Example 985-(4-Acetyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethylene)-thiazolidine-2,4-dione

Yield=43 mg (95%)

HPLC: 2.65 min. LC-MS: M/Z ESI: 1.12 min, 305.24 (M+1). ¹H NMR:(DMSO-d6) δ 12.58 (br. s, 1H), 8.30 (b s, 1H), 7.71 (s, 1H), 7.35 (d,J=9 Hz, 1H), 7.05 (d, J=9 Hz, 1H), 4.33 (t, J=6 Hz, 2H), 4.00 (t, J=6Hz, 2H).

Example 996-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-benzo[1,4]oxazine-4-carboxylicacid tert-butyl ester

Following the general method as outlined in Example 1, starting from6-Formyl-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester(intermediate 63) and 1,3-thiazolidine-2,4-dione, the title compound wasobtained.

HPLC: 4.23 min. LC-MS: M/Z ESI: 1.82 min, 359.16 (M−1). ¹H NMR:(DMSO-d6) δ 12.50 (br. s, 1H), 7.63 (d, J=3 Hz, 2H), 7.31 (d, J=3 Hz,1H), 6.95 (d, J=6 Hz, 1H), 6.30 (s, 2H).

Example 100[6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-3-oxo-2,3-dihydro-benzo[1,4]-oxazin-4-yl]-aceticacid methyl ester

Following the general method as outlined in Example 1, starting from(6-Formyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-acetic acid methylester (intermediate 64) and 1,3-thiazolidine-2,4-dione, the titlecompound was obtained.

HPLC: 2.83 min. LC-MS: M/Z ESI: 1.20 min, 347.25 (M−1). ¹H NMR:(DMSO-d6) δ 12.58 (br. s, 1H), 7.76 (s, 1H), 7.36 (s, 1H), 7.20 (m, 2H),4.82 (d, J=15 Hz, 4H), 3.71 (s, 3H).

Example 101N-Benzyl-2-[6-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl]-acetamide

[6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-3-oxo-2,3-dihydro-benzo[1,4]-oxazin-4-yl]-aceticacid methyl ester (195 mg, 0.56 mmol) (example 100) were saponifiedusing 2 eq. of LiOH as described for example 74 affording[6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl]-aceticacid. The so obtained acid (50 mg, 0.15 mmol) was dissolved in THF. HOBt(32 mg, 1.5 eq.), EDC (43 mg, 1.5 eq.) and benzylamine (25 mg, 1.5 eq.)were added while stirring. The reaction mixture was stirred for 15 h atrt. EtOAc was added and the organic phase was washed with 1N HCl,NaHCO₃, brine each of which three times. The crude residue afterevaporating the solvents was purified on silica gel using DCM/EtOAc aseluents to give the title compound as colourless powder (35 mg, 54%).

HPLC: 3.06 min. LC-MS: M/Z ESI: 1.27 min, 424.21 (M+1).

Example 1025-(4-Butyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethylene)-thiazolidine-2,4-dione

Following the general method as outlined in Example 1, starting from4-Butyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbaldehyde(intermediate 65) and 1,3-thiazolidine-2,4-dione, the title compound wasobtained.

HPLC: 3.67 min. LC-MS: M/Z ESI: 1.49 min. 331.23 (M−1). ¹H NMR:(DMSO-d6) δ 12.58 (br. s, 1H), 7.85 (s, 1H), 7.43 (s, 1H), 7.24 (d, J=6Hz, 1H), 7.15 (d, J=9 Hz, 1H), 4.73 (s, 2H), 3.91 (t, J=3 Hz, 2H), 1.57,(m, 2H), 1.36 (m, 2H), 0.91 (t, J=9 Hz, 3H).

Example 1035-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethylene)-thiazolidine-2,4-dione

Following the general method as outlined in Example 1, starting from4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbaldehyde(intermediate 66) and 1,3-thiazolidine-2,4-dione, the title compound wasobtained.

HPLC: 3.67 min. LC-MS: M/Z ESI: 1.46 min, 365.17 (M−1). ¹H NMR:(DMSO-d6) δ 12.58 (br. s, 1H), 7.68 (s, 1H), 7.38-7.22 (m, 8H), 5.24 (s,2H), 4.97 (s, 2H).

Example 104 5-(2-Chloro-benzofuran-5-ylmethylene)-thiazolidine-2,4-dione

Following the general method as outlined in Example 1, starting from2-Chloro-5-[1,3]dioxolan-2-yl-benzofurane (intermediate 67) and1,3-thiazolidine-2,4-dione, the title compound was obtained.

HPLC: 3.84 min. LC-MS: M/Z ESI: 1.62 min, 278.12 (M−1). ¹H NMR:(DMSO-d6) δ7.90-7.75 (M, 2H), 7.68 (d, j=9 Hz, 1H), 7.52 (d, J=9 Hz,1H), 7.09 (s, 1H).

Example 1055-(3-Amino-benzo[d]isoxazol-5-ylmethylene)-thiazolidine-2,4-dione

Following the general method as outlined in Example 1, starting from3-Amino-benzo[d]isoxazole-5-carbaldehyde (intermediate 68) and1,3-thiazolidine-2,4-dione, the title compound was obtained.

HPLC: 2.45 min. LC-MS: M/Z ESI: 0.97 min, 260.17 (M−1). ¹H NMR:(DMSO-d6) δ 12.60 (br. s, 1H), 8.01 (s, 1H), 7.85 (s, 1H), 7.60 (d, J=9Hz, 1H), 6.67 (s, 1H).

Example 1065-(3-Phenylethynyl-benzofuran-5-ylmethylene)-thiazolidine-2,4-dione

Following the general method as outlined in Example 1, starting from3-Phenylethynyl-benzofuran-5-carbaldehyde (intermediate 59) and1,3-thiazolidine-2,4-dione, the title compound was obtained.

HPLC: 4.82 min. LC-MS: M/Z ESI: 2.02 min, 344.18 (M−1). ¹H NMR:(DMSO-d6) δ 12.58 (br. s, 1H), 8.49 (s, 1H), 7.92 (s, 1H), 7.72 (d, J=9Hz, 1H), 7.62 (m, 3H), 7.45 (m, 4H).

Example 107 5-Benzo[1,2,5]thiadiazol-5-ylmethylene-thiazolidine-2,4-ione

Following the general method as outlined in Example 1, starting from2,1,3-Benzothiadiazole-5-carbaldehyde and 1,3-thiazolidine-2,4-dione,the title compound was obtained.

HPLC: 3.03 min. LC-MS: M/Z ESI: 1.14 min, 262.11 (M−1). ¹H NMR:(DMSO-d6) δ 12.58 (br. s, 1H), 8.11 (m, 2H), 7.90 (d, J=9 Hz, 1H), 7.47(s, 1H).

Example 108 5-Benzo[1,2,5]oxadiazol-5-ylmethylene-thiazolidine-2,4-ione

Following the general method as outlined in Example 1, starting from2,1,3-Benzoxadiazole-5-carbaldehyde and 1,3-thiazolidine-2,4-dione, thetitle compound was obtained.

HPLC: 3.02 min. LC-MS: M/Z ESI: 1.17 min, 246.17 (M−1). ¹H NMR:(DMSO-d6) δ 12.58 (br. s, 1H), 8.07 (m, 2H), 7.82 (d, J=9 Hz, 1H), 7.40(s, 1H).

Example 109 5-(2-Methyl-benzofuran-6-ylmethylene)-thiazolidine-2,4-dione

Following the general method as outlined in Example 1, starting from2-Methyl-5-[1,3]dioxolan-2-yl-benzofuran (intermediate 72) and1,3-thiazolidine-2,4-dione, the title compound was obtained afterpurification on reverse phase HPLC (solvents gradient H₂O/CH₃CN 0.1%TFA).

HPLC: 3.65 min, 90.75%. LC-MS: M/Z ESI: 1.65 min, 258.21 (M−1). ¹H NMR:(DMSO-d6) δ 12.45 (s1, 1H), 7.88 (s, 1H), 7.77 (d, 1H, J=1.5 Hz), 7.64(d, 1H, J=8.6 Hz), 7.47 (dd, 1H, J=8.6, 1.5 Hz), 6.69 (s, 1H), 2.37 (s,3H).

Example 1105-(2-Carboxymethyl-benzofuran-6-ylmethylene)-thiazolidine-2,4-dione

Following the general method as outlined in Example 1, starting from5-[1,3]Dioxolan-2-yl-benzofuran-2-carboxylic acid methyl ester(intermediate 73) and 1,3-thiazolidine-2,4-dione, the title compound wasobtained after purification on reverse phase HPLC (solvents gradientH₂O/CH₃CN 0.1% TFA).

HPLC: 3.32 min, 92.06%. LC-MS: M/Z ESI: 1.51 min, 302.19 (M−1). ¹H NMR:(DMSO-d6) δ 12.52 (s1, 1H), 7.97 (d, 1H, J=1.5 Hz), 7.82 (m, 3H), 7.69(dd, 1H, J=8.6, 1.5 Hz), 3.90 (s, 3H).

Example 1115-(3-Bromo-2-fluoro-2,3-dihydro-benzofuran-6-ylmethylene)-thiazolidine-2,4-dione

Following the general method as outlined in Example 1, starting from3-Bromo-2-fluoro-benzofuran-5-carbaldehyde (intermediate 74) and1,3-thiazolidine-2,4-dione, the title compound was obtained afterpurification on reverse phase HPLC (solvents gradient H₂O/CH₃CN 0.1%TFA).

HPLC: 3.66 min, 92.37%. LC-MS: M/Z ESI: 1.56 min, 343.09 (M−1). ¹H NMR:(DMSO-d6) δ 12.82 (s1, 1H), 8.00 (d, 1H, J=1.8 Hz), 7.88 (dd, 1H, J=8.5,1.8 Hz), 7.55 (d, 1H, J=8.5 Hz), 7.03 (d, 1H, ²J_(H-F)=59.5 Hz), 6.20(d, 1H, ³J_(H-F)=15.3 Hz). ¹⁹F NMR: (DMSO-d6) δ-114.66.

Example 112 5-(2-Fluoro-benzofuran-6-ylmethylene)-thiazolidine-2,4-dione

Following the general method as outlined in Example 1, starting from2-Fluoro-5-[1,3]dioxolan-2-yl-benzofuran (intermediate 75) and1,3-thiazolidine-2,4-dione, the title compound was obtained afterpurification on reverse phase HPLC (solvents gradient H₂O/CH₃CN 0.1%TFA).

HPLC: 3.67 min, 99.47%. LC-MS: M/Z ESI: 1.51 min, 262.14 (M−1). ¹H NMR:(DMSO-d6) δ 12.04 (s1, 1H), 7.89 (d, 1H, J=1.5 Hz), 7.83 (d, 1H, J=1.5Hz), 7.73 (d, 1H, J=8.6 Hz), 7.55 (dd, 1H, J=8.6, 1.5 Hz), 6.47 (d, 1H,³J_(H-F)=6.4 Hz). ¹⁹F NMR: (DMSO-d6) δ-111.28, −112.18.

Example 113 Preparation of a Pharmaceutical Formulation

The following formulation examples illustrate representativepharmaceutical compositions according to the present invention being notrestricted thereto.

Formulation 1—Tablets

A compound of formula (I) is admixed as a dry powder with a dry gelatinbinder in an approximate 1:2 weight ration. A minor amount of magnesiumstearate is added as a lubricant. The mixture is formed into 240-270 mgtablets (80-90 mg) of active azolidinone compound per tablet) in atablet press.

Formulation 2—Capsules

A compound of formula (I) is admixed as a dry powder with a starchdiluent in an approximate 1:1 weight ratio. The mixture is filled into250 mg capsules (125 mg of active azolidinone compound per capsule).

Formulation 3—Liquid

A compound of formula (I) (1250 mg), sucrose (1.75 g) and xanthan gum (4mg) are blended, passed through a No. 10 mesh U.S. sieve, and then mixedwith a previously prepared solution of microcrystalline cellulose andsodium carboxymethyl cellulose (11:89, 50 mg) in water. Sodium benzoate(10 mg), flavor, and color are diluted with water and added withstirring. Sufficient water is then added to produce a total volume of 5mL.

Formulation 4—Tablets

A compound of formula (I) is admixed as a dry powder with a dry gelatinbinder in an approximate 1:2 weight ratio. A minor amount of magnesiumstearate is added as a lubricant. The mixture is formed into 450-900 mgtablets (150-300 mg of active azolidinone compound) in a tablet press.

Formulation 5—Injection

A compound of formula (I) is dissolved in a buffered sterile salineinjectable aqueous medium to a concentration of approximately 5 mg/ml.

Example 114 Biological Assays

The compounds of the present invention may be subjected to the followingassays:

a) High Throughput PI3K Lipid Kinase Assay (Binding Assay):

The assay combines the scintillation proximity assay technology (SPA,Amersham) with the capacity of neomycin (a polycationic antibiotic) tobind phospholipids with high affinity and specificity. The ScintillationProximity Assay is based on the properties of weakly emitting isotopes(such as ³H, ¹²⁵I, ³³P). Coating SPA beads with neomycin allows thedetection of phosphorylated lipid substrates after incubation withrecombinant PI3K and radioactive ATP in the same well, by capturing theradioactive phospholipids to the SPA beads through their specificbinding to neomycin.

To a 384 wells MTP containing 5 μl of the test compound of formula (I)(solubilized in 6% DMSO; to yield a concentration of 100, 30, 10, 3, 1,0.3, 0.1, 0.03, 0.01, 0.001 μM of the test compound), the followingassay components are added. 1) 5 μl (58 ng) of Human recombinantGST-PI3Kγ (in Hepes 40 mM, pH 7.4, DTT 1 mM and ethyleneglycol 5%) 2) 10μl of lipid micelles and 3) 10 μl of Kinase buffer ([³³P]γATP 45 μM/60nCi, MgCl₂ 30 mM, DTT 1 mM, β-Glycerophosphate 1 mM, Na₃VO₄ 100 μM, NaCholate 0.3%, in Hepes 40 mM, pH 7.4). After incubation at roomtemperature for 180 minutes, with gentle agitation, the reaction isstopped by addition of 60 μl of a solution containing 100 μg ofneomycin-coated PVT SPA beads in PBS containing ATP 10 mM and EDTA 5 mM.The assay is further incubated at room temperature for 60 minutes withgentle agitation to allow binding of phospholipids to neomycin-SPAbeads. After precipitation of the neomycin-coated PVT SPA beads for 5minutes at 1500×g, radioactive PtdIns(3)P is quantified by scintillationcounting in a Wallac MicroBeta™ plate counter.

The values indicated in respect of PI3Kγ refer to the IC₅₀ (μM), i.e.the amount necessary to achieve 50% inhibition of said target. Saidvalues show a considerable potency of the azolidinone-vinylfused-benzene compounds with regard to PI3Kγ.

The tested compounds according to formula (I) display an inhibition(IC₅₀) with regard to PI3Kγ of less than 2 μM, more preferred equal orless than 1 μM.

Examples of inhibitory activities for test compounds 41, 61, 66, 73,103, 107 and 110 as set out in Table 1.

TABLE 1 IC₅₀ values of azolidinone-vinyl fused-benzene derivativesagainst PI3Kγ. Example No PI3Kγ, IC₅₀ (μM) 41 <1 61 <1 66 <1 73 <1 103<1 107 <1 110 <1b) Cell Based ELISA to Monitor PI3K Inhibition:

Measurement of Akt/PKB phosphorylation in macrophages after stimulationwith C5a: Raw 264: Raw 264-7 macrophages (cultured in DMEM-F12 mediumcontaining 10% Fetal Calf serum and antibiotics) are plated at 20'000cells/well in a 96 MTP 24 h before cell stimulation. Previous to thestimulation with 50 nM of Complement 5a (C5a; which is a well knownchemokine which stimulates the used cells) during 5 minutes, Cells areserum starved for 2 h, and pretreated with inhibitors for 20 minutes.After stimulation cells are fixed in 4% formaldehyde for 20 minutes andwashed 3 times in PBS containing 1% Triton X-100 (PBS/Triton).Endogenous peroxidase is blocked by a 20 minutes incubation in 0.6% H₂O₂and 0.1% Sodium Azide in PBS/Triton and washed 3 times in PBS/Triton.Cells are then blocked by 60 minutes incubation with 10% fetal calfserum in PBS/Triton. Next, phosphorylated Atk/PKB is detected by anovernight incubation at 4° C. with first antibody (anti phospho Serine473 Akt 1HC, Cell Signaling) diluted 800-fold in PBS/Triton, containing5% bovine serum albumin (BSA). After 3 washes in PBS/Triton, cells areincubated for 60 minutes with a peroxidase conjugated goat-anti-rabbitantibody (1/400 dilution in PBS/Triton, containing 5% BSA), washed 3times in PBS/Triton, and 2 times in PBS and further incubated in 100 μlof substrate reagent solution (R&D) for 20 minutes.

The reaction is stopped by addition of 50 μl of 1 M H₂SO₄ and absorbanceis read at 450 nm.

The values indicated reflect the percentage of inhibition of AKTphosphorylation as compared to basal level. Said values show a cleareffect of the azolidinone-vinyl fused-benzene compounds on theactivation of AKT phosphorylation in macrophages.

Compounds of examples 1, 19, 66 and 107, when used at 1 μM completely(about 100%) inhibit C5a-mediated AKT phosphorylation. Examples 17, 19or 73, when used at 1 μM, inhibit 95% of the C5a-mediatedAKT-phosphorylation.

1. A method for the treatment of inflammation, the method comprising,administering to a subject in need thereof, an effective amount of acompound of formula (I):

as well as its geometrical isomers, its optically active forms asenantiomers, diastereomers and its racemate forms, as well aspharmaceutically acceptable salts thereof, wherein A is a 5-8 memberedheterocyclic group; X is S or O; Y¹ and Y² are independently S or O; Zis S or O; R′ is H, CN, carboxy, acyl, C₁-C₆-alkoxy, halogen, hydroxy,acyloxy, C₁-C₆-alkyl carboxy, C₁-C₆-alkyl acyloxy, C₁-C₆-alkyl alkoxy,alkoxycarbonyl, C₁-C₆-alkyl alkoxycarbonyl, aminocarbonyl, C₁-C₆-alkylaminocarbonyl, acylamino, C₁C₆-alkyl acylamino, ureido, C₁-C₆-alkylureido, amino, C₁-C₆-alkyl amino, ammonium, sulfonyloxy, C₁-C₆-alkylsulfonyloxy, sulfonyl, C₁-C₆-alkyl sulfonyl, sulfinyl, C₁-C₆-alkylsulfinyl, sulfanyl, C₁-C₆-alkyl sulfanyl, sulfonylamino, C₁-C₆-alkylsulfonylamino or carbamate; R² is selected from the group consisting ofH, halogen, acyl, amino, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,C₁-C₆-alkyl carboxy, C₁-C₆-alkyl acyl, C₁-C₆-alkyl alkoxycarbonyl,C₁-C₆-alkyl aminocarbonyl, C₁-C₆-alkyl acyloxy, C₁-C₆-alkyl acylamino,C₁-C₆-alkyl ureido, C₁-C₆-alkyl amino, C₁-C₆-alkyl alkoxy, C₁-C₆-alkylsulfanyl, C₁-C₆-alkyl sulfinyl, C₁-C₆-alkyl sulfonyl, C₁-C₆-alkylsulfonylaminoaryl, aryl, C₃-C₈-cycloalkyl or heterocycloalkyl,C₁-C₆-alkyl aryl, C₂-C₆-alkenyl-aryl, C₂-C₆-alkynyl aryl, carboxy,cyano, hydroxy, C₁-C₆-alkoxy, nitro, acylamino, ureido, C₁-C₆-alkylcarbamate, sulfonylamino, sulfanyl, or sulfonyl; n is 0, 1 or 2; withthe proviso that the following compounds are excluded:

wherein R¹ is a lower alkyl or aralkyl and R² is H or a halogen.
 2. Themethod according to claim 1, wherein Y¹ and Y² are both oxygen.
 3. Themethod according to claim 1, wherein n is 1 or 2 and R¹ and R² are bothH.
 4. The method according to claim 1, wherein, in the compound offormula (I), X is S, Y¹ and Y² are both O, and n is
 0. 5. The methodaccording to claim 1, whereby the compound of formula (I) is athiazolidinone-vinyl fused-benzene of the formula (Ia)

wherein Y¹, R¹, R², Z and n are as above defined for the compound offormula (I); V and W are each, independently from each other, O, S or—NR³ wherein R³ is H or C₁-C₆ alkyl; G is a C₁-C₅ alkylene or a C₁-C₅alkenylene group; o and m are each, independently from each other, 0 or1; and q is an integer from 0 to
 4. 6. The method according to claim 5,whereby the thiazolidinone-vinyl fused-benzene has the formula (Ib):

wherein Y¹, R¹, R², V, Z, W, m, n, o, q are as above defined in thecompound of formula (Ia), and p is an integer from 1 to
 4. 7. The methodaccording to claim 5, whereby the thiazolidinone-vinyl fused-benzene hasthe formula (Ic):

wherein W, as well as R¹ and Y¹, are as above defined in the compound offormula (Ia).
 8. The method according to claim 5, whereby thethiazolidinone-vinyl fused-benzene has the formula (Id):

wherein R¹, R², Z and n are as above defined in formula (Ia); o is 0 or1; p is an integer from 1 to 4 and q is an integer from 0 to
 4. 9. Themethod according to claim 5, wherein, in formula (Ia), Z is O, m is 0, nis 1, p is 1 or 2, q is 1, and R¹ and R² are each as above defined forthe compound of formula (Ia).
 10. The method according to claim 5,wherein, in formula (Ia), m is 1, n is 0, p is 1 or 2, q is 0, and R¹and R² are each as above defined for the compound of formula (Ia). 11.The method according to claim 5, wherein, in formula (Ia), m is 0, n is1, p is 1 or 2, q is 0, and R¹ and R² are each as defined above for thecompound of formula (I).
 12. The method according to claim 5, wherein,in formula (Ia), R¹ is halogen or hydrogen.
 13. A thiazolidinone-vinylfused-benzene according to formula (II-a):

wherein A is selected from the group consisting of dioxol, dioxin,dihydrofuran, (dihydro) furanyl, (dihydro)oxazinyl, pyridinyl,isooxazolyl, oxazolyl (dihydro)napthalenyl, pyrimidinyl, triazolyl,imidazolyl, pyrazinyl, thiazolidinyl, thiadiazolyl, and oxadiazolyl; R²is selected from the group consisting of H, halogen, acyl, amino,C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkenyl, C₁-C₆-alkyl carboxy,C₁-C_(o)-alkyl acyl, C₁-C₆-alkyl alkoxycarbonyl, C₁-C₆-alkylaminocarbonyl, C₁-C_(o)-alkyl acyloxy, C₁-C₆-alkyl acylamino,C₁-C₆-alkyl ureido, C₁-C₆-alkyl carbamate, C₁-C₆-alkyl amino,C₁-C₆-alkyl alkoxy, C₁-C₆-alkyl sulfanyl, C₁-C₆-alkyl sulfinyl,C₁-C₆-alkyl sulfonyl, C₁-C₆-alkyl sulfonylaminoaryl, aryl,C₃-C₈-cycloalkyl or heterocycloalkyl, C₁-C₆-alkyl aryl,C₂-C₆-alkenyl-aryl, C₂-C₆-alkynyl aryl, carboxy, cyano, hydroxy,C₁-C₆-alkoxy, nitro, acylamino, ureido, sulfonylamino, sulfanyl, andsulfonyl.
 14. A thiazolidinone-vinyl fused-benzene according to formula(II):

as well as its geometrical isomers, its optically active forms asenantiomers, diastereomers and its racemate forms, as well aspharmaceutically acceptable salts thereof, wherein Y¹ is S or O; Z is Sor O; R¹ is H, CN, carboxy, acyl, C₁-C₆-alkoxy, halogen, hydroxy,acyloxy, C₁-C₆-alkyl carboxy, C₁-C₆-alkyl acyloxy, C₁-C₆-alkyl alkoxy,alkoxycarbonyl, C₁-C₆-alkyl alkoxycarbonyl, aminocarbonyl, C₁-C₆-alkylaminocarbonyl, acylamino, C₁-C₆-alkyl acylamino, ureido, C₁-C₆-alkylureido, amino, C₁-C₆-alkyl amino, ammonium, sulfonyloxy, C₁-C₆-alkylsulfonyloxy, sulfonyl, C₁-C₆-alkyl sulfonyl, sulfinyl, C₁-C₆-alkylsulfinyl, sulfanyl, C₁-C₆-alkyl sulfanyl, sulfonylamino, C₁-C₆-alkylsulfonylamino or carbamate; R² is selected from the group consisting ofH, halogen, acyl, amino, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,C₁-C₆-alkyl carboxy, C₁-C₆-alkyl acyl, C₁-C₆-alkyl alkoxycarbonyl,C₁-C₆-alkyl aminocarbonyl, C₁-C₆-alkyl acyloxy, C₁-C₆-alkyl acylamino,C₁-C₆-alkyl ureido, C₁-C₆-alkyl amino, C₁-C₆-alkyl alkoxy, C₁-C₆-alkylsulfanyl, C₁-C₆-alkyl sulfinyl, C₁-C₆-alkyl sulfonyl, C₁-C₆-alkylsulfonylaminoaryl, aryl, C₃-C₈-cycloalkyl or heterocycloalkyl,C₁-C₆-alkyl aryl, C₂-C₆-alkenyl-aryl, C₂-C₆-alkynyl aryl, carboxy,cyano, hydroxy, C₁-C₆-alkoxy, nitro, acylamino, ureido, C₁-C₆-alkylcarbamate, sulfonylamino, sulfanyl, and sulfonyl; n is 0 or
 1. 15. Thethiazolidinone-vinyl fused-benzene according to claim 14, wherein Y¹ isO.
 16. The thiazolidinone-vinyl fused-benzene according to claim 14,wherein R¹ is selected from the group consisting of C₁-C₆-alkyl,C₁-C₆-alkyl aryl, aryl, C₃-C₈-cycloalkyl or heterocycloalkyl,C₁-C₆-alkyl aryl, C₂-C₆-alkenyl-aryl and C₂-C₆-alkynyl aryl.
 17. Athiazolidinone-vinyl fused-benzene according to formula (III):

as well as its geometrical isomers, its optically active forms asenantiomers, diastereomers and its racemate forms, as well aspharmaceutically acceptable salts thereof, and wherein R¹ is H, CN,carboxy, acyl, C₁-C₆-alkoxy, halogen, hydroxy, acyloxy, C₁-C₆-alkylcarboxy, C₁-C₆-alkyl acyloxy, C₁-C₆-alkyl alkoxy, alkoxycarbonyl,C₁-C₆-alkyl alkoxycarbonyl, aminocarbonyl, C₁-C₆-alkyl aminocarbonyl,acylamino, C₁-C₆-alkyl acylamino, ureido, C₁-C₆-alkyl ureido, amino,C₁-C₆-alkyl amino, ammonium, sulfonyloxy, C₁-C₆-alkyl sulfonyloxy,sulfonyl, C₁-C₆-alkyl sulfonyl, sulfinyl, C₁-C₆-alkyl sulfinyl,sulfanyl, C₁-C₆-alkyl sulfanyl, sulfonylamino, C₁-C₆-alkyl sulfonylaminoor carbamate; R² is selected from the group consisting of H, halogen,acyl, amino, C₁-C₆-alkyl, C₂-C_(o)-alkenyl, C₂-C₆-alkynyl,C₁-C_(o)-alkyl carboxy, C₁-C₆-alkyl acyl, C₁-C₆-alkyl alkoxycarbonyl,C₁-C₆-alkyl aminocarbonyl, acyloxy, C₁-C₆-alkyl acylamino, C₁-C₆-alkylureido, C₁-C₆-alkyl amino, C₁-C₆-alkyl alkoxy, C₁-C₆-alkyl sulfanyl,C₁-C₆-alkyl sulfinyl, C₁-C₆-alkyl sulfonyl, C₁-C₆-alkylsulfonylaminoaryl, aryl, C₃-C₈-cycloalkyl or heterocycloalkyl,C₁-C₆-alkyl aryl, C₂-C₆-alkenyl-aryl, C₂-C₆-alkynyl aryl, carboxy,cyano, hydroxy, C₁-C₆-alkoxy, nitro, acylamino, ureido, C₁-C₆-alkylcarbamate, sulfonylamino, sulfanyl, and sulfonyl.
 18. Athiazolidinone-vinyl fused-benzene according any of formulae (IV), (V)and (VI):

wherein R¹ is selected from the group consisting of hydrogen, halogen,cyano, C₁-C₆-alkyl, C₁-C₆-alkoxy, acyl, and alkoxy cabonyl, and R² isselected from the group consisting of H, halogen, acyl, amino,C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-alkyl carboxy,C₁-C₆-alkyl acyl, C₁-C₆-alkyl alkoxycarbonyl, C₁-C₆-alkyl aminocarbonyl,C₁-C₆-alkyl acyloxy, C₁-C₆-alkyl acylamino, C₁-C₆-alkyl ureido,C₁-C₆-alkyl amino, C₁-C₆-alkyl alkoxy, C₁-C₆-alkyl sulfanyl, C₁-C₆-alkylsulfinyl, C₁-C₆-alkyl sulfonyl, C₁-C₆-alkyl sulfonylaminoaryl, aryl,C₃-C₈-cycloalkyl or heterocycloalkyl, C₁-C₆-alkyl aryl,C₂-C₆-alkenyl-aryl, C₂-C₆-alkynyl aryl, carboxy, cyano, hydroxy,C₁-C₆-alkoxy, nitro, acylamino, ureido, C₁-C₆-alkyl carbamate,sulfonylamino, sulfanyl, and sulfonyl.
 19. The thiazolidinone-vinylfused-benzene according to claim 13, selected from the group consistingof: 5-(1,3-benzodioxol-5-ylmethylene)-1,3-thiazolidine-2,4-dione,5-(1,3-benzodioxol-5-ylmethylene)-2-thioxo-1,3-thiazolidin-4-one,5-(2,3-dihydro-1,4-benzodioxin-6-ylmethylene)-1,3-thiazolidine-2,4-dione,5-(2,3-dihydro-1-benzofuran-5-ylmethylene)-1,3-thiazolidine-2,4-dione,5-[(7-methoxy-1,3-benzodioxol-5-yl)methylene]-1,3-thiazolidine-2,4-dione,5-[(9,10-dioxo-9,10-dihydroanthracen-2-yl)methylene]-1,3-thiazolidine-2,4-dione,(5-[(2,2-difluoro-1,3-benzodioxol-5-yl)methylene]-1,3-thiazolidine-2,4-dione,(5Z)-5-(1,3-dihydro-2-benzofuran-5-ylmethylene)-1,3-thiazolidine-2,4-dione,5-(1-benzofuran-5-ylmethylene)-1,3-thiazolidine-2,4-dione,5-[(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)methylene]-1,3-thiazolidine-2,4-dione,5-(1,3-benzodioxol-5-ylmethylene)-2-imino-1,3-thiazolidin-4-one,5-Quinolin-6-ylmethylene-thiazolidine-2,4-dione,5-Quinolin-6-ylmethylene-2-thioxo-thiazolidin-4-one,2-Imino-5-quinolin-6-ylmethylene-thiazolidin-4-one,5-(3-Methyl-benzo[d]isoxazol-5-ylmethylene)-thiazolidine-2,4-dione,5-(4-Phenyl-quinazolin-6-ylmethylene)-thiazolidine-2,4-dione,5-(4-Dimethylamino-quinazolin-6-ylmethylene)-thiazolidine-2,4-dione,5-[(4-aminoquinazolin-6-yl)methylene]-1,3-thiazolidine-2,4-dione,5-[(4-piperidin-1-ylquinazolin-6-yl)methylene]-1,3-thiazolidine-2,4-dione,5-[(4-morpholin-4-ylquinazolin-6-yl)methylene]-1,3-thiazolidine-2,4-dione,5-{[4-(benzylamino)quinazolin-6-yl]methylene}-1,3-thiazolidine-2,4-dione,5-{[4-(diethylamino)quinazolin-6-yl]methylene)-1,3-thiazolidine-2,4-dione,5-({4-[(pyridin-2-ylmethyl)amino]quinazolin-6-yl}methylene)-1,3-thiazolidine-2,4-dione,5-({4-[(pyridin-3-ylmethyl)amino]quinazolin-6-yl}methylene)-1,3-thiazolidine-2,4-dione,ethyl1-{6-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]quinazolin-4-yl}piperidine-3-carboxylate,ethyl1-{6-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]quinazolin-4-yl)piperidine-4-carboxylate,tert-butyl-1-{6-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]quinazolin-4-yl)-L-prolinate,5-{[4-(4-methylpiperazin-1-yl)quinazolin-6-yl]methylene}-1,3-thiazolidine-2,4-dione,5-{[4-(4-pyrimidin-2-ylpiperazin-1-yl)quinazolin-6-yl]methylene}-1,3-thiazolidine-2,4-dione,5-({4-[4-(4-fluorophenyl)piperidin-1-yl]quinazolin-6-yl}methylene)-1,3-thiazolidine-2,4-dione,5-{[4-(4-benzylpiperidin-1-yl)quinazolin-6-yl]methylene}-1,3-thiazolidine-2,4-dione,5-({4-[4-(2-phenylethyl)piperidin-1-yl]]quinazolin-6-yl}methylene)-1,3-thiazolidine-2,4-dione,5-{[4-(4-methylpiperidin-1-yl)quinazolin-6-yl]methylene}-1,3-thiazolidine-2,4-dione,5-{[4-(4-hydroxypiperidin-1-yl)quinazolin-6-yl]methylene}-1,3-thiazolidine-2,4-dione,1-[6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-quinazolin-4-yl]-piperidine-4-carboxylicacid,1-[6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-quinazolin-4-yl]-piperidine-3-carboxylicacid,1-[6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-quinazolin-4-yl]-pyrrolidine-2-carboxylicacid, 5-(4-Methylamino-quinazolin-6-ylmethylene)-thiazolidine-2,4-dione,5-(4-Methoxy-quinazolin-6-ylmethylene)-thiazolidine-2,4-dione2-Imino-5-(4-methylamino-quinazolin-6-ylmethylene)-thiazolidin-4-one,2-Imino-5-(4-piperidine-quinazolin-6-ylmethylene)-thiazolidin-4-one,2-Imino-5-(4-dimethylamino-quinazolin-6-ylmethylene)-thiazolidin-4-one,5-(2-Methyl-2H-benzotriazol-5-ylmethylene)-thiazolidine-2,4-dione,5-(3-Methyl-3H-benzotriazol-5-ylmethylene)-thiazolidine-2,4-dione,5-(3-Ethyl-3H-benzoimidazol-5-ylmethylene)-thiazolidine-2,4-dione,5-{[1-(4-phenylbutyl)-1H-benzimidazol-6-yl]methylene}-1,3-thiazolidine-2,4-dione,5-[(1-prop-2-yn-1-yl-H-benzimidazol-6-yl)methylene]-1,3-thiazolidine-2,4-dione,5-[(1-{2-[4-(trifluoromethyl)phenyl]ethyl}-1H-benzimidazol-6-yl)methylene]-1,3-thiazolidine-2,4-dione,5-([1-{2-(4-hydroxyphenyl)ethyl]-1H-benzimidazol-6-yl}methylene)-1,3-thiazolidine-2,4-dione,methyl4-{6-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1H-benzimidazol-1-yl}cyclohexanecarboxylate,5-({1-[2-(5-methoxy-1H-indol-3-yl)ethyl]-1H-benzimidazol-6-yl}methylene)-1,3-thiazolidine-2,4-dione,5-({1-[(1-methyl-1H-pyrazol-4-yl)methyl]-1H-benzimidazol-6-yl}methylene)-1,3-thiazolidine-2,4-dione,5-({1-[2-(3,4-dimethoxyphenyl)ethyl]-1H-benzimidazol-6-yl}methylene)-1,3-thiazolidine-2,4-dione,5-({1-[2-(4-phenoxyphenyl)ethyl]-1H-benzimidazol-6-yl}methylene)-1,3-thiazolidine-2,4-dione,5-({1-[4-(trifluoromethyl)benzyl]-1H-benzimidazol-6-yl}methylene)-1,3-thiazolidine-2,4-dione,4-{6-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1H-benzimidazol-1-yl}cyclohexanecarboxylicacid,5-[(1-isobutyl-1H-benzimidazol-6-yl)methylene]-1,3-thiazolidine-2,4-dione,5-({1-[2-(1,3-benzodioxol-4-yl)ethyl]-1H-benzimidazol-6-yl}methylene)-1,3-thiazolidine-2,4-dione,5-({1-[2-(2-phenoxyphenyl)ethyl]-1H-benzimidazol-6-yl}methylene)-1,3-thiazolidine-2,4-dione,5-{[1-(3,3-diphenylpropyl)-1H-benzimidazol-6-yl]methylene}-1,3-thiazolidine-2,4-dione,5-{[1-(2-methoxybenzyl)-1H-benzimidazol-6-yl]methylene}-1,3-thiazolidine-2,4-dione,5-{[1-(3-furylmethyl)-1H-benzimidazol-6-yl]methylene}-1,3-thiazolidine-2,4-dione,5-[(1-propyl-1H-benzimidazol-6-yl)methylene]-1,3-thiazolidine-2,4-dione,5-Quinoxalin-6-ylmethylene-thiazolidine-2,4-dione,5-Quinoxalin-6-ylmethylene-2-thioxo-thiazolidin-4-one,2-Imino-5-quinoxalin-6-ylmethylene-thiazolidin-4-one,5-Benzothiazol-6-ylmethylene-thiazolidine-2,4-dione,5-(3-Methyl-benzofuran-5-ylmethylene)-thiazolidine-2,4-dione,5-(2-Bromo-3-methyl-benzofuran-5-ylmethylene)-thiazolidine-2,4-dione,5-(3-bromo-benzofuran-5-ylmethylene)-thiazolidine-2,4-dione,3-[5-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-benzofuran-3-yl]-acrylicacid ethyl ester,3-[5-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-benzofuran-3-yl]-acrylicacid,5-[3-(3-oxo-3-piperidin-1-yl-propenyl)-benzofuran-5-ylmethylene]-thiazolidine-2,4-dione,Methyl1-((3-{5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1-benzofuran-3-yl}prop-2-enoyl)prolinate,Methyl1-((3-{5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1-benzofuran-3-yl}prop-2-enoyl)-D-prolinate,(5-({3-[(3-oxo-3-pyrrolidin-1-ylprop-1-en-1-yl]-1-benzofuran-5-yl}methylene)-1,3-thiazolidine-2,4-dione,5-({3-[3-morpholin-4-yl-3-oxoprop-1-en-1-yl]-1-benzofuran-5-yl}methylene)-1,3-thiazolidine-2,4-dione,Methyl1-(3-{5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1-benzofuran-3-yl}prop-2-enoyl)-L-prolinate,N-cyclohexyl-3-{5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1-benzofuran-3-yl)-N-methylacrylamide,3-{5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1-benzofuran-3-yl}-N-ethyl-N-(2-hydroxyethyl)acrylamide,N-cyclobutyl-3-{5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1-benzofuran-3-yl}acrylamide,5-({3-[3-azetidin-1-yl-3-oxoprop-1-en-1-yl]-1-benzofuran-5-yl}methylene)-1,3-thiazolidine-2,4-dione,5-({3-[3-(1,3-dihydro-2H-isoindol-2-yl)-3-oxoprop-1-en-1-yl]-1-benzofuran-5-yl}methylene)-1,3-thiazolidine-2,4-dione,5-({3-[3-azepan-1-yl-3-oxoprop-1-en-1-yl]-1-benzofuran-5-yl}methylene)-1,3-thiazolidine-2,4-dione,3-{5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1-benzofuran-3-yl}-N-piperidin-1-ylacrylamide,3-{5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1-benzofuran-3-yl}-N-(pyridin-3-ylmethyl)acrylamide,N-cyclohexyl-3-{5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1-benzofuran-3-yl}acrylamide,5-({3-[3-(4-methylpiperazin-1-yl)-3-oxoprop-1-en-1-yl]-1-benzofuran-5-yl}methylene)-1,3-thiazolidine-2,4-dione,N-cycloheptyl-3-{5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1-benzofuran-3-yl}acrylamide,5-({3-[3-(2,5-dihydro-1H-pyrrol-1-yl)-3-oxoprop-1-en-1-yl]-1-benzofuran-5-yl}methylene)-1,3-thiazolidine-2,4-dione,N-cyclopentyl-3-{5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-1-benzofuran-3-yl}acrylamide,3-[5-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-benzofuran-3-yl]-propionicacid ethyl ester,3-[5-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-benzofuran-3-yl]-propionicacid,5-[3-(3-oxo-3-piperidin-1-yl-propyl)-benzofuran-5-ylmethylene]-thiazolidine-2,4-dione,6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-2,3-dihydro-benzo[1,4]oxazine-4-carboxylicacid tert-butyl ester,5-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethylene)-thiazolidine-2,4-dione,5-(4-Benzoyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethylene)-thiazolidine-2,4-dione,5-(4-Acetyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethylene)-thiazolidine-2,4-dione,6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-benzo[1,4]oxazine-4-carboxylicacid tert-butyl ester,[6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-3-oxo-2,3-dihydro-benzo[1,4]-oxazin-4-yl]-aceticacid methyl ester,N-Benzyl-2-[6-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl]-acetamide,5-(4-Butyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethylene)-thiazolidine-2,4-dione,5-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethylene)-thiazolidine-2,4-dione,5-(2-Chloro-benzofuran-5-ylmethylene)-thiazolidine-2,4-dione,5-(3-Amino-benzo[d]isoxazol-5-ylmethylene)-thiazolidine-2,4-dione,5-(3-Phenylethynyl-benzofuran-5-ylmethylene)-thiazolidine-2,4-dione,5-Benzo[1,2,5]thiadiazol-5-ylmethylene-thiazolidine-2,4-dione,5-Benzo[1,2,5]oxadiazol-5-ylmethylene-thiazolidine-2,4-dione,5-(2-Methyl-benzofuran-6-ylmethylene)-thiazolidine-2,4-dione,5-(2-Carboxymethyl-benzofuran-6-ylmethylene)-thiazolidine-2,4-dione,5-(3-Bromo-2-fluoro-2,3-dihydro-benzofuran-6-ylmethylene)-thiazolidine-2,4-dione,and 5-(2-Fluoro-benzofuran-6-ylmethylene)-thiazolidine-2,4-dione.
 20. Amethod of preparing a medicament, comprising, contacting thethiazolidinone-vinyl fused-benzene according to claim 13, with one ormore pharmaceutically acceptable additives.
 21. A pharmaceuticalcomposition, comprising at least one thiazolidinone-vinyl fused-benzeneaccording to claim 13, and a pharmaceutically acceptable carrier,diluent or excipient thereof.
 22. A method for the treatment ofinflammation, the method comprising administering to a subject in needthereof, an effective amount of the thiazolidinone-vinyl fused-benzeneaccording to claim
 13. 23. A method of preparing a thiazolidinone-vinylfused-benzene of formula (II), according to claim 14, comprising thefollowing step:

wherein R¹, R², Y¹, Z and n are as above defined in formula (II).
 24. Amethod of preparing a thiazolidinone-vinyl fused-benzene of formula(III), according to claim 17, comprising the following step:

wherein R¹, R² are as above defined for formula (III), and Y¹ is 0, S orNH.
 25. A composition, comprising, a pharmaceutically acceptablecarrier, diluent or excipient and at least one compound according toformula (I):

as well as its geometrical isomers, its optically active forms asenantiomers, diastereomers and its racemate forms, as well aspharmaceutically acceptable salts thereof, wherein A is a 5-8 memberedheterocyclic group; X is S or O; Y¹ and Y² are independently S or O; Zis S or O; R¹ is H, CN, carboxy, acyl, C₁-C₆-alkoxy, halogen, hydroxy,acyloxy, C₁-C₆-alkyl carboxy, C₁-C₆-alkyl acyloxy, alkoxy,alkoxycarbonyl, C₁-C₆-alkyl alkoxycarbonyl, aminocarbonyl, C₁-C₆-alkylaminocarbonyl, acylamino, C₁-C₆-alkyl acylamino, ureido, C₁-C₆-alkylureido, amino, C₁-C₆-alkyl amino, ammonium, sulfonyloxy, C₁-C₆-alkylsulfonyloxy, sulfonyl, sulfonyl, sulfinyl, C₁-C₆-alkyl sulfinyl,sulfanyl, C₁-C₆-alkyl sulfanyl, sulfonylamino, C₁-C₆-alkyl sulfonylaminoor carbamate; R² is selected from the group consisting of H, halogen,acyl, amino, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-alkylcarboxy, C₁-C_(o)-alkyl acyl, C₁-C_(o)-alkyl alkoxycarbonyl, C₁-C₆-alkylaminocarbonyl, C₁-C₆-alkyl acyloxy, C₁-C₆-alkyl acylamino, C₁-C₆-alkylureido, C₁-C₆-alkyl amino, C₁-C₆-alkyl alkoxy, C₁-C₆-alkyl sulfanyl,C₁-C₆-alkyl sulfinyl, C₁-C₆-alkyl sulfonyl, C₁-C₆-alkylsulfonylaminoaryl, aryl, C₃-C₈-cycloalkyl or heterocycloalkyl,C₁-C_(o)-alkyl aryl, C₂-C₆-alkenyl-aryl, C₂-C₆-alkynyl aryl, carboxy,cyano, hydroxy, C₁-C₆-alkoxy, nitro, acylamino, ureido, C₁-C₆-alkylcarbamate, sulfonylamino, sulfanyl, or sulfonyl; n is 0, 1 or 2; withthe proviso that the following compounds are excluded:

wherein R¹ is a lower alkyl or aralkyl and R² is H or a halogen.